Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

Shohreh Majd; John Power; Hugh Grantham

doi:10.1186/s12868-015-0211-1

Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

Majd, Shohreh; Power, John; Grantham, Hugh 2015-10-23 00:00:00 Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deteriora- tion and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed. Keywords: Alzheimer’s disease, Parkinson’s disease, Beta-amyloid, Alpha-synuclein, Intracellular signalling, Neurotoxicity, Neurodegeneration Pathophysiology of toxic proteins Background All the proteins implicated in neurodegenerative diseases Protein misfolding and aggregation contribute to the share the common pattern of dysfunctional structure pathophysiology of neurodegenerative disorders such as due to an unusual folding [5–7]. Through folding, pro - Alzheimer’s (AD) and Parkinson’s diseases (PD). In physi- teins acquire the three dimensional structures required ological situations protein misfolding is sensed by the cel- to undertake their biological functions. This process is lular control systems as a threat which is then followed prone to errors, causing the protein not to acheive its by an immediate response. Any delay detecting the mis- functional structure, building a toxic protein deposition. folded proteins, may result in damage and progression of When an aggregation status is established, disaggregation neurodegenerative disorders [1, 2]. Unfortunately, not all rarely occurs because under physiological conditions, the cellular responses to misfolded proteins are neuro- the equilibrium is in favour of aggregation [8–11]. These protective. Activation of some intracellular pathways as a early aggregates are believed to be the source of toxicity part of this response occasionally create further damage, in neurodegenerative disorders. interruption in synaptic connections and neuronal apop- tosis [3, 4]. Alzheimer’s disease (AD) AD is the most common form of dementia and among the leading causes of death in adults. AD is associ- *Correspondence: shohreh.majd@flinders.edu.au Centre for Neuroscience and Paramedic Unit, School of Medicine, ated with two main lesions: extracellular plaques made Flinders University of South Australia, Adelaide, SA 5042, Australia of beta-amyloid (Aβ) and intracellular neurofibrillary Full list of author information is available at the end of the article © 2015 Majd et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Majd et al. BMC Neurosci (2015) 16:69 Page 2 of 13 tangles (NFT) made of tau protein [12, 13]. The plaques was obtained for both Aβ 1-40 and 1–42, two of the most are the consequences of abnormal protein folding and toxic forms of amyloid protein [35, 36]. aggregation with direct and indirect toxic effects on neu - Aβ oligomers can be generated both extra- and intra- ronal survival [14, 15]. cellularly. Extracellular Aβ toxicity could be mediated through binding to receptors such as NMDA and dis- Aβ biochemical structure and toxicity rupting the calcium balance of the neuron [37, 38]. Extra- Aβ, the principle protein implicated in development of cellular Aβ is internalized, stored in the lysosomes and AD, is derived from amyloid precursor protein (APP). can leak into the cytosol by destabilization of the lyso- More than ten isoforms of the protein are characterized some membrane. Aβ oligomers have the ability to inhibit by different lengths of amino acid chains, and among the function of proteasomes causing neuronal apopto- them APP695 is exclusively expressed in neurons. The sis [39, 40]. Toxicity of fibrillar and oligomers of Aβ also transmembrane region of APP is placed near the c-termi- occurs through cytoskeletal disruption, tangle develop- nus, and contains a Kunitz-type protease inhibitor (KPI) ment, loss of synapses and inhibition of hippocampal domain, which acts as a potent inhibitor of coagulation long-term potentiation (LTP). This is the so-called “Aβ factors IXa and XIa, however, APP695 lacks the KPI cascade theory” of AD [12, 41, 42]. domain [16, 17]. Intracellular inclusions of Aβ have been found within APP can act as a receptor for a signalling glycoprotein neuronal compartments. [43, 44]. Internalization of F-spondin that is released by neurons and possesses roles Aβ occurs either via binding to low-density lipopro- in axonal guidance, neuronal differentiation and neuro- tein related protein-2 (LRP2) [45], LRP-1 [46, 47] or to repair [18, 19]. Some other functions of APP have also a receptor for advanced glycation end-product (RAGE) been proposed, including serving as a link between kine- [48]. The presence of Aβ in various subcellular com - sin and synaptic vesicles being an adhesion protein, a role partments, suggests different sites for APP proteolysis, in metal ion homeostasis, neuroprotection and a func- such as Aβ40 in the trans-Golgi network and Aβ42 in tion relating to promotion of neurite growth [16, 20]. the endoplasmic reticulum (ER) [49, 50] as well as Golgi APP is degraded in lysosomes [21–23] (Fig. 1). Aβ is compartments [51]. Autophagic vacuoles enriched with produced when a normal cleavage of APP occurs α and β presenilin-1 (PS1), APP and Aβ are found frequently in secretase cleave APP, outside the membrane. Also three degenerating neurons in patients with AD. This suggests members of a family of peptidase proteins, ADAM, (a an essential role for autophagy in clearing the aggregated disintegrin and metalloproteinase) have a recognized peptide through a lysosomal-dependent pathway [52]. role cleaving the extracellular portion of APP, in the same Aβ disrupts APP trafficking, and initiates a pathological way that α-secretase does [24]. Proteolysis of APP by cascade of Aβ accumulation [39, 43]. An accumulation of β-secretase cleaves APP695 after Met-596 and produces vacuoles filled with Aβ occurs as a result of interruption a large soluble N-terminal (sAPPβ) and a small mem- to neuronal trafficking associated with the disruption of brane-bound C-terminal fragment (C99), sAPPβ, is neu- autopghgosomes [53]. Aβ itself is also able to activate the roprotective and regulates synaptic plasticity. This larger adenosine monophosphate kinase (AMPK) pathway, gen- fragment of APP can also act as a microtubule associated erating more autophagic vacuoles [54]. Thus, AD patients protein (MAP) [25]. appear to produce abundant extracellular Aβ, resulting APP can undergo proteolysis at the cell surface. Its C99 in plaque formation with a high level of toxicity causing fragment can be processed by γ- secretase, presenilin 1 extensive neuronal apoptosis [55–57]. and 2, γ-secretase produces Aβ isoforms of 1-40, 1-42 or 1-43 [17, 26–28]. These peptides are made throughout Aß and kinases life, but in AD they accumulate due to either increased Glycogen synthase kinase‑3 beta (GSK‑3β) production or decreased degradation or removal. Glycogen synthase kinase-3 beta (GSK-3β) is well-known Remaining Aβ has the potential to enhance its own pro- for its role in glycogen metabolism, activation of tran- duction in cerebrovascular smooth muscles and hip- scription factors and phosphorylation of tau. GSK3 is pocampal neurons [29, 30]. Excess peptides, particular modulated through a variety of pathways including wnt, those of Aβ 1-40, 1-42 and 1-43, form toxic aggregates, phosphatidylinositide-3 kinase (PI3K) and Akt deacti- which result in progression of AD [16, 31, 32]. vate GSK-3β by phosphorylating Ser9 [58, 59], increasing Filaments of amyloid structure are approximately GSK-3β, in pre-tangles which is closely associated with 10 nm wide and 0.1–10 μm long with a β-sheet struc- tangle-bearing neurons suggesting a role in tau hyper- ture in their motif [33, 34]. Using Electron Paramagnetic phosphorylation in AD [60–64]. A recent report associ- Resonance Spectroscopy (EPRS) the β-sheet structure ated GSK-3β gene variants with the level of tau and Aβ42 Majd et al. BMC Neurosci (2015) 16:69 Page 3 of 13 Fig. 1 Cellular trafficking of APP and Aβ. APP cleavage to peptides occurs both in lysosomes after its endocytosis and at the surface of cell mem- brane. The proteolysis products accumulate intracellularly or are released into extracellular space in cerebrospinal fluid in AD as well as cognitive function pathway [74, 75]. MAPKs are a family of serine/threo- [65]. Further in vivo evidence of GSK-3β’s role in AD has nine kinases that contribute to the hyperprocessing of come from transgenic mouse models over-expressing this APP and hyper-phosphorylation of tau associated with kinase with a presentation of tau hyper-phosphorylation, AD [76, 77]. MAPKs phosphorylate proteins with regula- astrocytosis, and neuronal death [66, 67]. The concurrent tory functions including other kinases, transcription fac- hyper-phosphorylation of other cellular structures such tors and enzymes [78–80]. Stimulation of MAPK by Aβ as presinilines, β-catenin and GSK3-cAMP responsive in a Ras-dependent manner, leads to tau phosphorylation element-binding protein also produces some of the path- [81–84]. It has also been demonstrated that activation of ological features of AD [61, 68, 69]. MAPK by neurotrophins as well as Aβ induces p35, the Aβ exposure induces GSK-3β activity, extensive phos- specific activator of cyclin dependent kinase 5 (cdk5) in phorylation of tau and cell death. Aβ inhibits PI3K and the cell cycle. Thus another means of damaging the neu - Akt pathways and inactivates the wnt cascade,. Because ron through MAPK activation by Aβ could be re-activa- these pathways eventually deactivate GSK3, their inhibi- tion of the cell cycle, which is considered a lethal event tion will result in hyperactivity of GSK3 [70, 71] (Fig. 2). for neurons [78–85]. This Aβ-induced GSK-3β hyperactivity triggers the mito - chondrial fragmentation leading to neuronal apoptosis Aß, cytoskeleton and axonal transport [72]. GSK-3β also interacts with pyruvate dehydrogenase A constant interaction between microtubules and MAPs (PDH), thereby reducing levels of acetyl-CoA [73]. such as tau is a necessary element for axonal transport [86]. Tau holds the microtubular tracks in place and plays Mitogen‑activated protein kinases (MAPK) a key role in their stability [87]. When tau is subjected Aβ affects another intracellular second messenger the to hyper-phosphorylation, it loses the ability to bind to extracellular signal regulated Kinase (ERK)/MAPK microtubules and to maintain their structure, causing tau Majd et al. BMC Neurosci (2015) 16:69 Page 4 of 13 Fig. 2 Aβ and GSK3. Aβ binding to membrane receptors such as insulin receptor (IR) inhibits the activity of Akt and wnt through PI3K inhibition. Inactivation of Akt and wnt consequently dephosphorylate GSK3 which causes tau hyper-phosphorylation and microtubular disorganisation aggregation into paired helical filaments (PHF) and NFTs Aβ and apolipoprotein E (apoE) [88]. The number of NFTs is linked to the degree of demen - ApoE is a normal constituent of cells. In the nervous tia, suggesting a correlation between NFT, dystrophic neu- system, it acts as the main lipid transport protein with a rite formation and neuronal dysfunction [89–91]. It seems wide variety of roles in intracellular signalling, immune that interrupting axonal transport will interrupt neuronal modulation, glucose metabolism, lipid movement and function and lead to eventual death [92–94]. lipoprotein metabolism [102]. ApoE has been detected in Deposition of Aβ plaques precedes tau phosphoryla- the amyloid plaques in AD [103]. tion and exerts a damaging effect upon the cytoskeleton The ability of ApoE to interact with Aβ, demonstrated giving rise to PHF formation. [41]. Intraneuronal for- its critical role in amyloid deposition and clearance [91, mation of Aβ also happens prior to appearance of PHF, 102, 104]. The apoE4 allele of ApoE is associated with making it the upstream step in triggering the neurode- high cholesterol in cardiovascular disease and particu- generative events [95, 96]. larly AD, however, the apoE2 allele confers some protec- Further evidence that Aβ formation precedes PHF for- tion against hypercholesterolemia [102, 105, 106]. ApoE2 mation comes from a tau mutation study when tau muta- and E3 formed stable complexes with Aβ at levels of 20 tion produced tau-inclusion tangles but not plaques, fold greater than those occurring with apoE4 [107]. The however, APP or presenilin mutations caused both greater affinity of ApoE2 and E3 for Aβ protects neurons plaques and tangles. Transgenic mice doubly mutant for from neurotoxic effects of Aβ by facilitating the uptake mutant APP and tau have more tangles than mice with of these complexes by apoE receptors. Conversely, apoE4 the single mutant tau transgene [97, 98]. Tau phospho- accelerates Aβ deposition and progression/growth of Aβ rylation occurs through activation of c-Jun N-terminal seeds to larger Aβ plaques [108, 109]. kinase (JNK), a member of MAPK [99]. In a study, amy- loid injections exacerbated tangle pathology in mutant- Aβ, mitochondria and oxidative stress tau mice but why Aβ injections did not stimulate tau The central role of Aβ isoforms, in elevating free radi - pathology with wild-type tau is not known [100], when cal levels and oxidative stress led to the introduction of other transgenic mice overexpressing wild-type tau an Aβ-oxidative stress model for neurotoxicity in AD exhibited tangles [101]. [110–112]. Majd et al. BMC Neurosci (2015) 16:69 Page 5 of 13 Post-mortem studies revealed a wide range of [126]. Oxidative stress also elicits an inflammatory Aβ-derived mitochondrial dysfunction in AD patients response [127] through microglial activation [128, 129] [113–115]. Intracellular Aβ can be localized to mito- and release of pro inflammatory cytokines [130], promot - chondrial membranes, where it interrupts the normal ing inflammation and invasion of Aβ plaques by astro - mitochondrial function through blocking mitochondrial cytes [131] which mature plaques into neuritic plaques, a channels and inhibiting mitochondrial protein activ- common finding in AD patients. ity. By blocking the electron transport chain, Aβ accu- mulation leads to an increase in reactive oxygen species Aβ and cell cycle (ROS), causing oxidative stress [114, 116–118] (Fig. 3) Inappropriate cell cycle activation is an early event seen which leads to a deregulation of the ROS signalling path- in AD brains [132]. Although adult neurons are con- way in AD [119]. Superoxide radicals, produced due to sidered to be in a terminally-differentiated state, accu - mitochondrial dysfunction oxidate different neuronal mulation of associated cell cycle-related proteins have compartments such as proteins, lipids and DNA [117, been described in degenerating neurons [133–137]. It 120]. The evidence of oxidative damage in patients with is assumed that ectopic localization of cyclins, cyclin- mild cognitive dementia (MCD) shows that the oxida- dependent kinases (cdks) and cdk inhibitors are the tion insult occurs as one of the first steps of AD [121]. results of abortive attempt by neurons to re-enter the cell Chronic oxidative stress inhibits tau dephosphorylation cycle. Re-entering the cell cycle is a consequence of mito- by inhibiting tau phosphatase as well as increasing the gen factors and perhaps is promoted by the recruitment phosphorylation of tau by activating p38 [119]. of mitogenic signal transduction mechanisms [138, 139]. The other aspect of oxidative stress relates to pro - Subjecting neurons to Aβ, forces the cell to re-enter the tein oxidation. Oxidative modification of proteins is cell cycle, cross the G1/S phase transition and begin de important in aging and age-related neurodegenerative novo DNA synthesis before apoptotic death occurs [140– disorders [122]. Protein oxidation results in protein dys- 142], this could be inhibited by cell-cycle inhibitors [143, function associated with conformational changes. The 144]. These findings led to the hypothesis that vulner - oxidized protein may also have a higher resistance to pro- able neurons re-enter the cell cycle and proceed through teolysis and protein cross-linking and aggregation will be S phase, but then abort somatic division and eventually increased [123]. The aggregated misfolded proteins then degenerate [145]. get trapped in proteasome’s pore leading to proteasomal dysfunction [124, 125]. A vicious cycle of misfolded pro- Parkinson’s disease (PD) tein accumulation is then established. Parkinson’s disease (PD) is the second most common Aggregated peptides have the potential to initiate oxi- neurodegenerative disorder among the adults. The pro - dative stress through cellular dysfunction leading to cal- gressive impaired motor function in patients with PD is cium accumulation and increased tau polymerization an outcome of dopaminergic neuronal loss particularly in the substantia nigra (SN) [146]. A common finding from degenerating dopaminergic cells includes intracellular inclusions of particles, known as Lewy bodies (LBs) [147, 148]. The major component of LBs is the fibrillar form of α-Syn and this suggests the role of protein misfolding in Parkinson’s pathology [149, 150]. α‑Synuclein structure and toxicity α-Syn is an acidic synaptic protein (14 kDa), which is expressed in a wide range of tissues including the brain [151–153]. α-Syn retains the ability of building a β-sheet structure after prolonged incubation due to its posses- sion of a hydrophobic region of amino acids from 66 to 95 [154]. As a vesicle associated protein, the main func- Fig. 3 Aβ and mitochondrial dysfunction. Attachment of Aβ to inner tions of α-Syn are regulating membrane stability, neu- membrane of mitochondria alters the different aspects of mitochon- ronal plasticity, synaptic rearrangement, controlling drial activity. Blocking electron chain through reducing complex IV activity, damaging mitochondrial DNA (mtDNA), inhibiting tricarbo- vesicular trafficking and neurotransmission through a xylic acid ( TCA) cycle and ATP production, enhancing cytochrome chaperon-like function to other proteins [134, 155–159]. c release and activation of apoptotic pathways, and increasing the Due to the ability α-Syn to interact with tubulin, α-Syn mitochondria production of ROS are some of the examples also shows a microtubule-associated activity [160–162]. Majd et al. BMC Neurosci (2015) 16:69 Page 6 of 13 Lesions from autopsied PD brains show a marked decreased MTT levels, reduction of glutathione and high increase in S129 hyperphosphorylated α-Syn [163] which levels of iron, in brain tissue confirmed the presence of creates high molecular weight α-Syn with a high poten- oxidative stress as a common finding in PD [189–193] 2+ tial for self-assembly. This makes it a likely candidate to Oxidative stress affects the Ca shift and balance in be a toxic protein in the event of aggregation [164, 165]. cytoplasm, leading to stimulation of mitochondrial nitric α-Syn could also be phosphorylated on Tyr39 with no oxide synthase (mtNOS) [194, 195]. α-Syn also has the link between this phosphorylation and pathological fea- ability of binding to pro apoptotic protein BAD, a mem- tures [166]. ber of Bcl-2 family [182]. As the result of this attachment, Fibrillar α-Syn as the main component of LBs, is pre- Bcl-2 protein is removed from mitochondrial pores, sent in many dying cells in PD [167], however, oligomeric allowing cytochrome c to be released from the mito- α-Syn also possesses enough toxicity to damage neu- chondria. This event triggers neuronal apoptosis dem - rons [168]. The process of misfolding of α-Syn has been onstrating a link between mitochondrial dysfunction and shown to be accelerated by many metals such as copper synaptic accumulation of α-Syn in PD [195, 196]. [169] and ferric ion and also by elevated intracellular cytochrome c [170]. Conformational changes leads to α‑Synuclein and axonal trafficking protein misfolding reduce the ability of α-Syn to inter- α-Syn ability to act as a MAP, allows microtubules to act with the vesicular trafficking and modulating neuro - maintain their stability, to carry cargos in an energy- transmission [171–174]. Conformational changes and dependent manner, and to facilitate neurotransmitter consequent aggregation α-Syn also triggers a cascade of release [159, 161]. Overexpression and phosporylation neuronal response such as autophagy, one of the main of α-Syn, however, affects the normal function of ER pathways of α-Syn degradation [175, 176]. and Golgi system. α-Syn directly binds to ER and the Golgi apparatus and inhibits the soluble NSF attach- α‑Synuclein and MAPK ment protein receptor (SNARE) complex assembly [197, Regulation of MAPK pathway is a downstream effect of 198]. The SNARE complex is made of vesicular SNARE α-Syn. In neurons, α-Syn binding to MAPK inhibits this proteins (v-SNARE) and target membrane SNARE pro- pathway. In particular, α-Syn binds directly to ERK2 and teins (t-SNARE). It possesses the ability of self-assembly indirectly to Elk-1, which is also an ERK2 substrate [177]. and allows vesicular fusion to cell membrane [199, 200]. u Th s α-Syn reduces dopamine transporter (DAT) inser - Blocking this assembly by α-Syn overexpression inter- tion in the synaptic membranes of axonal terminals [178]. feres with neurotransmitter release and reuptake (Fig. 4). α-Syn also decreases MAPK activation through reducing Consequently, relocating cellular proteins within the cell the phosphorylation of p38 and down regulating c-fos or from the cell toward the membrane and eventual neu- gene [179, 180]. rotransmission will be disturbed [201]. The eventual out - Phosphorylation and accumulation of MAPK elements come would include protein accumulation inside the cell, have been reported in PD patients [81, 172]. One of the Golgi system fragmentation, a decrease in neurotrans- MAPK elements is JNK, that is phosphorylated in PD and mitter release and neuronal apoptosis [202–204]. α-Syn activates the transcription factor of c-jun. Activation of also reduces polymerization of tubulin. Whether reduc- c-jun increases the level of cell death genes expression in ing polymerization of tubulin is a direct outcome or an dopaminergic neurons [82, 181]. JNK also inhibits Bcl-2 indirect one, through generating mitochondrial dysfunc- survival protein by activation of pro-apoptotic proteins tion and lack of ATP for polymerization, the outcome of Bad and Bim [182, 183]. The misregulation of MAPK represents itself as a disrupted axonal transport and neu- eventually leads to neuronal apoptosis. Inhibiting JNK rite degeneration [20, 203, 205]. phosphorylation, however, can protect neurons from death [184]. Activation of ERK has also been reported in α‑Syn and Aβ interaction glial cells which consequently starts a cascade of inflam - Both AD and PD show similar clinical presentations in matory responses and blocking that pathway reduces their mid to late stages [206, 207] suggesting the possibil- microglial activation [185, 186]. ity of interaction between α-Syn and Aβ [25, 144, 208]. It has been shown that instead of immediate cell death, α‑Synuclein and oxidative stress affected neurons live for several months in a near- func - α-Syn overexpression causes the impairment of mito- tional state [209, 210]. Constant production of both pro- chondrial homeostasis [187] leading to oxidative stress teins allows continuing protein–protein interaction and and dopamine oxidation [188]. Formation of giant as a result, a reciprocal induction between α-Syn and Aβ mitochondria and laminated bodies, autophagozomes, could cause a gradual increase in the protein levels of Majd et al. BMC Neurosci (2015) 16:69 Page 7 of 13 Fig. 4 α-Syn in normal condition binds to synaptic vesicle membrane and also v-SNARE. v-SNARE assembly to t-SNARE creates SNARE complex and results in synaptic vesicle fusion to cell membrane and neurotransmitter release. α-Syn clusters synaptic vesicles in the axonal terminal and produces a high concentration of presynaptic vesicles at a certain area of plasma membrane. Vesicular α-Syn also binds to early endosomes and facilitates neurotransmitter refilling of vesicles. α-Syn accumulation/fibrilation inhibits vesicular refilling, blocks SNARE complex formation and reduces the number of docking neurotransmitter vesicles Abbreviations both types, before neurodegeneration commences [144]. Aβ: beta-amyloid; AD: Alzheimer’s disease; apoE: apolipoprotein E; APP: amy- The PI3K pathway and ApoE could contribute to this loid precursor protein; α-Syn: alpha-synuclein; cdk: cyclin dependent kinase; interaction, as manipulation of PI3K reduced the recipro- ER: endoplasmic reticulum; ERK: extracellular signal regulated kinase; GSK-3β: glycogen synthase kinase-3 Beta; JNK: Jun N-terminal kinase; KPI: Kunitz-type cal elevation of α-Syn and Aβ [144]. Deletion of ApoE in protease inhibitor; LBs: Lewy bodies; LRP2: low-density lipoprotein related pro- α-Syn transgenic mice decreased the levels of Aβ, thereby tein-2; LTP: long-term potentiation; MAPK: mitogen-activated protein kinases; alleviating the onset of disease [211]. More research is mtNOS: mitochondrial nitric oxide synthase; NFT: neurofibrillary tangles; NGF: nerve growth factor; PD: Parkinson’s disease; PDH: pyruvate dehydrogenase; still required to achieve a complete understanding of the PHF: paired helical filaments; PI3K: phosphatidylinositide-3kinase; RAGE: glyca- underlying mechanisms. tion end-product; ROS: reactive oxygen species; SN: substantia nigra; SNARE: NSF attachment protein receptor; t-SNARE: target membrane SNARE protein; v-SNARE: vesicular SNARE protein. Conclusion Although the process of neuronal death is a common Authors’ contributions feature in AD and PD, the underlying mechanisms are SM, HG and JP conceived and drafted the manuscript. All authors read and approved the final manuscript. still under investigation. Some aspects of toxicity may be specific for a distinct type of neurodegenerative disorder Author details however common cellular mechanisms with a substan- Centre for Neuroscience and Paramedic Unit, School of Medicine, Flinders University of South Australia, Adelaide, SA 5042, Australia. Department tial overlap underlie the neuronal responses to the toxic of Human Physiology, School of Medicine, Flinders University of South Aus- proteins. tralia, Adelaide, SA 5042, Australia. In conclusion, neuronal death in neurodegenera- Acknowledgements tive disorders is not a single-cause event and establish- SM was a member of Alzheimer’s and Parkinson’s lab at Flinders University of ing the exact links between the activation mechanisms South Australia when she started writing the manuscript and we would like to in response to toxic proteins could open a window for thank the lab members for their enthusiastic discussions about protein toxicity in neurodegenerative disorders. promising therapeutic interventions. Majd et al. BMC Neurosci (2015) 16:69 Page 8 of 13 Competing interests 21. Gouras GK, Xu H, Jovanovic JN, Buxbaum JD, Wang R, Greengard P, The authors declare that they have no competing interests. Relkin NR, Gandy S. Generation and regulation of beta-amyloid peptide variants by neurons. J Neurochem. 1998;71(5):1920–5. Received: 12 January 2015 Accepted: 13 October 2015 22. Schneider A, Rajendran L, Honsho M, Gralle M, Donnert G, Wouters F, Hell SW, Simons M. Flotillin-dependent clustering of the amyloid pre- cursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci. 2008;28(11):2874–82. 23. Sarajarvi T, Tuusa JT, Haapasalo A, Lackman JJ, Sormunen R, Helisalmi S, Roehr JT, Parrado AR, Makinen P, Bertram L, et al. Cysteine 27 vari- References ant of the delta-opioid receptor affects amyloid precursor protein 1. Uversky VN. Protein folding revisited. A polypeptide chain at the processing through altered endocytic trafficking. Mol Cell Biol. folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol 2011;31(11):2326–40. Life Sci. 2003;60(9):1852–71. 24. Wang X, Huang T, Bu G, Xu H. Dysregulation of protein trafficking in 2. Stefani M, Rigacci S. Protein folding and aggregation into amyloid: neurodegeneration. Mol Neurodegenr. 2014;9(31):1–9. the interference by natural phenolic compounds. Int J Mol Sci. 25. Olah J, Vincze O, Virok D, Simon D, Bozso Z, Tokesi N, Horvath I, Hla- 2013;14(6):12411–57. vanda E, Kovacs J, Magyar A, et al. Interactions of pathological hallmark 3. Kakizuka A. Protein precipitation: a common etiology in neuro-degen- proteins: tubulin polymerization promoting protein/p25, beta-amyloid, erative disorders? Trends Genet. 1998;14(10):396–402. and alpha-synuclein. J Biol Chem. 2011;286(39):34088–100. 4. Kopito RR, Ron D. Conformational disease. Nat Cell Biol. 26. Howlett DR, Simmons DL, Dingwall C, Christie G. In search of an 2000;2(11):E207–9. enzyme: the beta-secretase of Alzheimer’s disease is an aspartic pro- 5. Karpinar DP, Balija MB, Kugler S, Opazo F, Rezaei-Ghaleh N, Wender N, teinase. Trends Neurosci. 2000;23(11):565–70. Kim HY, Taschenberger G, Falkenburger BH, Heise H, et al. Pre-fibrillar 27. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, alpha-synuclein variants with impaired beta-structure increase neuro- Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and toxicity in Parkinson’s disease models. EMBO J. 2009;28(20):3256–68. tetrapeptide release from the transmembrane domain of beta-carboxyl 6. Borgia MB, Borgia A, Best RB, Steward A, Nettels D, Wunderlich B, terminal fragment. J Neurosci. 2009;29(41):13042–52. Schuler B, Clarke J. Single-molecule fluorescence reveals sequence-spe - 28. Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M. Familial cific misfolding in multidomain proteins. Nature. 2011;474(7353):662–5. Alzheimer’s disease mutations inhibit gamma-secretase-mediated lib- 7. Norrby E. Prions and protein-folding diseases. J Intern Med. eration of beta-amyloid precursor protein carboxy-terminal fragment. J 2011;270(1):1–14. Neurochem. 2005;94(5):1189–201. 8. Stefani M. Protein misfolding and aggregation: new examples in medi- 29. Davis-Salinas J, Saporito-Irwin SM, Cotman CW, Van Nostrand WE. cine and biology of the dark side of the protein world. Biochim Biophys Amyloid beta-protein induces its own production in cultured Acta. 2004;1739(1):5–25. degenerating cerebrovascular smooth muscle cells. J Neurochem. 9. Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding: 1995;65(2):931–4. gain- and loss-of-function in neurodegenerative diseases. EMBO J. 30. Majd S, Rastegar K, Zarifkar A, Takhshid MA. Fibrillar beta-amyloid 2008;27(2):336–49. (Abeta) (1-42) elevates extracellular Abeta in cultured hippocampal 10. Abelein A, Bolognesi B, Dobson CM, Graslund A, Lendel C. Hydropho- neurons of adult rats. Brain Res. 2007;1185:321–7. bicity and conformational change as mechanistic determinants for 31. Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, nonspecific modulators of amyloid beta self-assembly. Biochemistry. Vingtdeux V, van de Steeg E, Ret G, Canton T, et al. Massive CA1/2 2012;51(1):126–37. neuronal loss with intraneuronal and N-terminal truncated Abeta42 11. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. accumulation in a novel Alzheimer transgenic model. Am J Pathol. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2004;165(4):1289–300. 2013;125(6):777–94. 32. Yamamoto K, Shimada H, Koh H, Ataka S, Miki T. Serum levels of 12. Selkoe DJ. Toward a comprehensive theory for Alzheimer’s disease. albumin-amyloid beta complexes are decreased in Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumula- Geriatr Gerontol Int. 2014;14(3):716–23. tion and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 33. Sunde M, Blake CC. From the globular to the fibrous state: protein struc- 2000;924:17–25. ture and structural conversion in amyloid formation. Q Rev Biophys. 13. Kumar S, Wirths O, Theil S, Gerth J, Bayer TA, Walter J. Early intraneu- 1998;31:1–39. ronal accumulation and increased aggregation of phosphorylated 34. Benzinger TL, Gregory DM, Burkoth TS, Miller-Auer H, Lynn DG, Botto RE, Abeta in a mouse model of Alzheimer’s disease. Acta Neuropathol. Meredith SC. Propagating structure of Alzheimer’s beta-amyloid(10-35) 2013;125(5):699–709. is parallel beta-sheet with residues in exact register. Proc Natl Acad Sci 14. Lansbury PT Jr. Structural neurology: are seeds at the root of neuronal USA. 1998;95:13407–12. degeneration? Neuron. 1997;19(6):1151–4. 35. Tycko R. Insights into the amyloid folding problem from solid-state 15. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts NMR. Biochemistry. 2003;42:3151–9. A, Ohno M, Disterhoft J, Van Eldik L, et al. Intraneuronal beta-amyloid 36. Torok M, Milton S, Kayed R, Wu P, McIntire T, Glabe CG, Langen R. Struc- aggregates, neurodegeneration, and neuron loss in transgenic mice tural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils with five familial Alzheimer’s disease mutations: potential factors in studied by site-directed spin labeling. J Biol Chem. 2002;277:40810–5. amyloid plaque formation. J Neurosci. 2006;26(40):10129–40. 37. Yanagisawa K. Role of gangliosides in Alzheimer’s disease. Biochim 16. Storey E, Cappai R. The amyloid precursor protein of Alzheimer’s disease Biophys Acta. 2002;1768:1943–51. and the Abeta peptide. Neuropathol Appl Neurobiol. 1999;25(2):81–97. 38. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, 17. Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta- and Klein WL. Abeta oligomers induce neuronal oxidative stress through an gamma- secretases. FEBS Lett. 2000;483(1):6–10. N-methyl-d -aspartate receptor-dependent mechanism that is blocked 18. Ho A, Sudhof TC. Binding of F-spondin to amyloid-beta precursor by the Alzheimer drug memantine. J Biol Chem. 2002;282:11590–601. protein: a candidate amyloid-beta precursor protein ligand that modu- 39. Laferla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer’s lates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci USA. disease. Nat Rev Neurosci. 2007;8:499–509. 2004;101(8):2548–53. 40. Almeida CG, Takahashi RH, Gouras GK. Beta-amyloid accumulation 19. Schubert D, Klar A, Park M, Dargusch R, Fischer WH. F-spondin promotes impairs multivesicular body sorting by inhibiting the ubiquitin-proteas- nerve precursor differentiation. J Neurochem. 2006;96(2):444–53. ome system. J Neurosci. 2006;26:4277–88. 20. Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS. Axonal transport of 41. Huse JT, Doms RW. Closing in on the amyloid cascade: recent amyloid precursor protein is mediated by direct binding to the kinesin insights into the cell biology of Alzheimer’s disease. Mol Neurobiol. light chain subunit of kinesin-I. Neuron. 2000;28(2):449–59. 2000;22(1–3):81–98. Majd et al. BMC Neurosci (2015) 16:69 Page 9 of 13 42. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic brains staged for Alzheimer disease neurofibrillary changes. J Neuro - approaches to Alzheimer’s disease. Brain. 2006;129(Pt 11):2840–55. pathol Exp Neurol. 1999;58(9):1010–9. 43. Wertkin AM, Turner RS, Pleasure SJ, Golde TE, Younkin SG, Trojanowski 64. Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K. JQ, Lee VM. Human neurons derived from a teratocarcinoma cell line Preferential labeling of Alzheimer neurofibrillary tangles with antisera express solely the 695-amino acid amyloid precursor protein and pro- for tau protein kinase ( TPK) I/glycogen synthase kinase-3 beta and duce intracellular beta- amyloid or A4 peptides. Proc Natl Acad Sci USA. cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol. 1993;90(20):9513–7. 1996;92(3):232–41. 44. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal 65. Kettunen P, Larsson S, Holmgren S, Olsson S, Minthon L, Zetterberg H, MF, Xu H, Greengard P, Gouras GK. Intraneuronal Alzheimer abeta42 Blennow K, Nilsson S, Sjölander A. Genetic variants of GSK3B are associ- accumulates in multivesicular bodies and is associated with synaptic ated with biomarkers for Alzheimer’s disease and cognitive function. J pathology. Am J Pathol. 2002;161(5):1869–79. Alzheimers Dis. 2015;44(4):1313–22. 45. Alvira-Botero X, Perez-Gonzalez R, Spuch C, Vargas T, Antequera D, 66. Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Garzon M, Bermejo-Pareja F, Carro E. Megalin interacts with APP and Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, et al. Glycogen the intracellular adapter protein FE65 in neurons. Mol Cell Neurosci. synthase kinase-3beta phosphorylates protein tau and rescues the 2010;45(3):306–15. axonopathy in the central nervous system of human four-repeat tau 46. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, transgenic mice. J Biol Chem. 2000;275(52):41340–9. Bu G. Amyloid precursor protein regulates brain apolipoprotein E and 67. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. cholesterol metabolism through lipoprotein receptor LRP1. Neuron. Decreased nuclear beta-catenin, tau hyperphosphorylation and 2007;56(1):66–78. neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 47. Spuch C, Ortolano S, Navarro C. LRP-1 and LRP-2 receptors function 2001;20(1–2):27–39. in the membrane neuron. Trafficking mechanisms and proteolytic 68. Hansen T, Rehfeld JF, Nielsen FC. GSK-3beta reduces cAMP-induced processing in Alzheimer’s disease. Front Physiol. 2012;3:269. cholecystokinin gene expression by inhibiting CREB binding. NeuroRe- 48. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, port. 2004;15(5):841–5. McKhann G, Funatsu Y, Nakamichi N, et al. RAGE-mediated signalling 69. Jope RS, Yuskaitis CJ, Beurel E. Glycogen synthase kinase-3 (GSK3): contributes to intraneuronal transport of amyloid-beta and neuronal inflammation, diseases, and therapeutics. Neurochem Res. dysfunction. Proc Natl Acad Sci USA. 2009;106(47):20021–6. 2007;32(4–5):577–95. 49. Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee 70. Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal VM, Doms RW. Alzheimer’s Abeta(1-42) is generated in the endoplas- transduction cascades common to the insulin receptor pathway. J Biol mic reticulum/intermediate compartment of NT2N cells. Nat Med. Chem. 2007;282(46):33305–12. 1997;3(9):1021–3. 71. Magdesian MH, Carvalho MM, Mendes FA, Saraiva LM, Juliano MA, 50. Greenfield JP, Tsai J, Gouras GK, Hai B, Thinakaran G, Checler F, Sisodia Juliano L, Garcia-Abreu J, Ferreira ST. Amyloid-beta binds to the extra- SS, Greengard P, Xu H. Endoplasmic reticulum and trans-Golgi network cellular cysteine- rich domain of Frizzled and inhibits Wnt/beta-catenin generate distinct populations of Alzheimer beta-amyloid peptides. Proc signaling. J Biol Chem. 2008;283(14):9359–68. Natl Acad Sci USA. 1999;96(2):742–7. 72. Yan J, Liu XH, Han MZ, Wang YM, Sun XL, Yu N, Li T, Su B, Chen ZY. Block- 51. Sudoh S, Kawamura Y, Sato S, Wang R, Saido TC, Oyama F, Sakaki Y, age of GSK3β-mediated Drp1 phosphorylation provides neuroprotec- Komano H, Yanagisawa K. Presenilin 1 mutations linked to familial tion in neuronal and mouse models of Alzheimer’s disease. Neurobiol Alzheimer’s disease increase the intracellular levels of amyloid beta-pro- Aging. 2015;36(1):211–27. tein 1-42 and its N-terminally truncated variant(s) which are generated 73. Imahori K, Uchida T. Physiology and pathology of tau protein kinases in at distinct sites. J Neurochem. 1998;71(4):1535–43. relation to Alzheimer’s disease. J Biochem. 1997;121(2):179–88. 52. Nah J, Yuan J, Jung YK. Autophagy in neurodegenerative diseases: from 74. Echeverria V, Ducatenzeiler A, Dowd E, Janne J, Grant SM, Szyf M, Wan- mechanism to therapeutic approach. Mol Cells. 2015;38(5):381–9. dosell F, Avila J, Grimm H, Dunnett SB, et al. Altered mitogen-activated 53. UamekKozio M, Furmaga-Jaboska W, Januszewski S, Brzozowska J, protein kinase signaling, tau hyperphosphorylation and mild spatial Scilewska M, Jaboski M, Pluta R. Neuronal autophagy: self-eating or self- learning dysfunction in transgenic rats expressing the beta-amyloid cannibalism in Alzheimer’s disease. Neurochem Res. 2013;38:1769–73. peptide intracellularly in hippocampal and cortical neurons. Neurosci- 54. Son SM, Jung ES, Shin HJ, Byun J, Mook-Jung I. Aβ-induced formation ence. 2004;129(3):583–92. of autophagosomes is mediated by RAGECaMKK β-AMPK signaling. 75. Espana J, Gimenez-Llort L, Valero J, Minano A, Rabano A, Rodriguez- Neurobiol Aging. 2012;33:1006.e11–23. Alvarez J, LaFerla FM, Saura CA. Intraneuronal beta-amyloid accumula- 55. Bayer TA, Wirths O, Majtenyi K, Hartmann T, Multhaup G, Beyreuther K, tion in the amygdala enhances fear and anxiety in Alzheimer’s disease Czech C. Key factors in Alzheimer’s disease: beta-amyloid precursor pro- transgenic mice. Biol Psychiatry. 2010;67(6):513–21. tein processing, metabolism and intraneuronal transport. Brain Pathol. 76. Trojanowski JQ, Mawal-Dewan M, Schmidt ML, Martin J, Lee VM. Locali- 2001;11(1):1–11. zation of the mitogen activated protein kinase ERK2 in Alzheimer’s 56. Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman disease neurofibrillary tangles and senile plaque neurites. Brain Res. CW. Apoptosis is induced by beta-amyloid in cultured central nervous 1993;618(2):333–7. system neurons. Proc Natl Acad Sci USA. 1993;90(17):7951–5. 77. Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke- 57. Versen LL, Mortishire-Smith RJ, Pollack SJ, Shearman MS. The toxicity Iqbal I. Up- regulation of mitogen-activated protein kinases ERK1/2 in vitro of beta-amyloid protein. Biochem J. 1995;311(Pt 1):1–16. and MEK1/2 is associated with the progression of neurofibril- 58. Parihar MS, Hemnani T. Alzheimer’s disease pathogenesis and therapeu- lary degeneration in Alzheimer’s disease. Brain Res Mol Brain Res. tic interventions. J Clin Neurosci. 2004;11(5):456–67. 2002;109(1–2):45–55. 59. Hoshi M, Takashima A, Noguchi K, Murayama M, Sato M, Kondo S, 78. Harada T, Morooka T, Ogawa S, Nishida E. ERK induces p35, a neuron- Saitoh Y, Ishiguro K, Hoshino T, Imahori K. Regulation of mitochondrial specific activator of Cdk5, through induction of Egr1. Nat Cell Biol. pyruvate dehydrogenase activity by tau protein kinase I/glycogen syn- 2001;3(5):453–9. thase kinase 3beta in brain. Proc Natl Acad Sci USA. 1996;93(7):2719–23. 79. Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family 60. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase of protein kinases with diverse biological functions. Microbiol Mol Biol kinase-3. Trends Biochem Sci. 2004;29(2):95–102. Rev. 2004;68(2):320–44. 61. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s 80. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, disease. J Neurochem. 2008;104(6):1433–9. Fumagalli S, Kozma SC, Thomas G. S6K1(−/−)/S6K2(−/−) mice exhibit 62. Gomez-Sintes R, Hernandez F, Lucas JJ, Avila J. GSK-3 mouse models to perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine study neuronal apoptosis and neurodegeneration. Front Mol Neurosci. mRNA translation and reveal a mitogen-activated protein kinase- 2011;4:45. dependent S6 kinase pathway. Mol Cell Biol. 2004;24(8):3112–24. 63. Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. 81. Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gomez C, Ambrosio Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in S. Active, phosphorylation-dependent mitogen-activated protein Majd et al. BMC Neurosci (2015) 16:69 Page 10 of 13 kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal 102. Saunders AM. Apolipoprotein E and Alzheimer disease: an update kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and on genetic and functional analyses. J Neuropathol Exp Neurol. Dementia with Lewy bodies. J Neural Transm. 2001;108(12):1383–96. 2000;59(9):751–8. 82. Ferrer I, Blanco R, Carmona M, Puig B. Phosphorylated mitogen-acti- 103. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone vated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), protein in patients with cerebral and systemic amyloid. Neurosci Lett. stress- activated protein kinase (SAPK/JNK-P), and calcium/calmodulin- 1992;135(2):235–8. dependent kinase II (CaM kinase II) are differentially expressed in tau 104. Fleming LM, Weisgraber KH, Strittmatter WJ, Troncoso JC, Johnson deposits in neurons and glial cells in tauopathies. J Neural Transm. GV. Differential binding of apolipoprotein E isoforms to tau and other 2001;108(12):1397–415. cytoskeletal proteins. Exp Neurol. 1996;138(2):252–60. 83. Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative 105. Ly S, Altman R, Petrlova J, Lin Y, Hilt S, Huser T, Laurence TA, Voss JC. foldopathies. Biochim Biophys Acta. 2005;1739(2–3):298–310. Binding of apolipoprotein E inhibits the oligomer growth of amyloid- 84. Lambourne SL, Sellers LA, Bush TG, Choudhury SK, Emson PC, Suh YH, beta peptide in solution as determined by fluorescence cross-correla- Wilkinson LS. Increased tau phosphorylation on mitogen-activated tion spectroscopy. J Biol Chem. 2013;288(17):11628–35. protein kinase consensus sites and cognitive decline in transgenic 106. Smith JD. Apolipoprotein E4: an allele associated with many diseases. models for Alzheimer’s disease and FTDP-17: evidence for distinct Ann Med. 2000;32(2):118–27. molecular processes underlying tau abnormalities. Mol Cell Biol. 107. Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz 2005;25(1):278–93. GS. Lipoproteins in the central nervous system. Ann N Y Acad Sci. 85. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;903:167–75. 2000;407(6805):802–9. 108. Carter DB, Dunn E, McKinley DD, Stratman NC, Boyle TP, Kuiper SL, 86. Brown A. Axonal transport of membranous and nonmembranous Oostveen JA, Weaver RJ, Boller JA, Gurney ME. Human apolipoprotein cargoes: a unified perspective. J Cell Biol. 2003;160(6):817–21. E4 accelerates beta-amyloid deposition in APPsw transgenic mouse 87. Mandelkow E, Song YH, Schweers O, Marx A, Mandelkow EM. On the brain. Ann Neurol. 2001;50(4):468–75. structure of microtubules, tau, and paired helical filaments. Neurobiol 109. Cho KH, Durbin DM, Jonas A. Role of individual amino acids of apolipo- Aging. 1995;16(3):347–54. protein A-I in the activation of lecithin: cholesterol acyltransferase and 88. Iqbal K, Alonso AC, Gong CX, Khatoon S, Pei JJ, Wang JZ, Grundke-Iqbal in HDL rearrangements. J Lipid Res. 2001;42(3):379–89. I. Mechanisms of neurofibrillary degeneration and the formation of 110. Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer’s neurofibrillary tangles. J Neural Transm Suppl. 1998;53:169–80. amyloid beta-peptide-associated free radical oxidative stress and 89. Brion JP. Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol. neurotoxicity. J Struct Biol. 2000;130(2–3):184–208. 1998;40(3):130–40. 111. Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress 90. Dickson TC, King CE, McCormack GH, Vickers JC. Neurochemical diver- and neurotoxicity: implications for neurodegeneration in Alzheimer’s sity of dystrophic neurites in the early and late stages of Alzheimer’s disease brain. A review. Free Radic Res. 2002;36(12):1307–13. disease. Exp Neurol. 1999;156(1):100–10. 112. Butterfield DA, Griffin S, Munch G, Pasinetti GM. Amyloid beta-peptide 91. Vickers JC, Dickson TC, Adlard PA, Saunders HL, King CE, McCormack and amyloid pathology are central to the oxidative stress and inflam- G. The cause of neuronal degeneration in Alzheimer’s disease. Prog matory cascades under which Alzheimer’s disease brain exists. J Neurobiol. 2000;60(2):139–65. Alzheimers Dis. 2002;4(3):193–201. 92. Masliah E, Terry RD, DeTeresa RM, Hansen LA. Immunohistochemical 113. Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, quantification of the synapse-related protein synaptophysin in Alzhei- Obrenovich ME, Perry G, Smith MA. Role of mitochondrial dysfunction mer disease. Neurosci Lett. 1989;103(2):234–9. in Alzheimer’s disease. J Neurosci Res. 2002;70(3):357–60. 93. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. Comparison 114. Spuch C, Ortolano S, Navarro C. New insights in the amyloid-Beta of neurodegenerative pathology in transgenic mice overexpressing interaction with mitochondria. J Aging Res. 2012;2012:324968. V717F beta-amyloid precursor protein and Alzheimer’s disease. J Neu- 115. Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mito- rosci. 1996;16(18):5795–811. chondrial targeting and a novel transmembrane arrest of Alzheimer’s 94. Henriques AG, Vieira SI, da Cruz ESEF, da Cruz ESOA. Abeta promotes amyloid precursor protein impairs mitochondrial function in neuronal Alzheimer’s disease-like cytoskeleton abnormalities with consequences cells. J Cell Biol. 2003;161(1):41–54. to APP processing in neurons. J Neurochem. 2010;113(3):761–71. 116. Miranda S, Opazo C, Larrondo LF, Munoz FJ, Ruiz F, Leighton F, Inestrosa 95. Braak H, Del Tredici K. Alzheimer’s disease: intraneuronal altera- NC. The role of oxidative stress in the toxicity induced by amyloid beta- tions precede insoluble amyloid-beta formation. Neurobiol Aging. peptide in Alzheimer’s disease. Prog Neurobiol. 2000;62(6):633–48. 2004;25(6):713–8 (discussion 743–716). 117. DiCiero Miranda M, de Bruin VM, Vale MR, Viana GS. Lipid peroxidation 96. Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Serrano J, Bentura and nitrite plus nitrate levels in brain tissue from patients with Alzhei- ML, Martinez-Murillo R, Martinez A, Rodrigo J. Intra- and extracellular mer’s disease. Gerontology. 2000;46(4):179–84. Abeta and PHF in clinically evaluated cases of Alzheimer’s disease. 118. Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Histol Histopathol. 2004;19(3):823–44. Bradshaw PC. Mitochondrial amyloid-beta levels are associated with 97. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, the extent of mitochondrial dysfunction in different brain regions and Sahara N, Skipper L, Yager D, et al. Enhanced neurofibrillary degen- the degree of cognitive impairment in Alzheimer’s transgenic mice. J eration in transgenic mice expressing mutant tau and APP. Science. Alzheimers Dis. 2010;20(Suppl 2):S535–50. 2001;293(5534):1487–91. 119. Lloret A, Fuchsberger T, Giraldo E, Vina J. Molecular mechanisms link- 98. Mudher A, Lovestone S. Alzheimer’s disease-do tauists and baptists ing amyloid β toxicity and Tau hyperphosphorylation in Alzheimer’s finally shake hands? Trends Neurosci. 2002;25(1):22–6. disease. Free Radic Biol Med. 2015;83:186–91. 99. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, 120. Reddy PH. Amyloid precursor protein-mediated free radicals and oxida- Hudspeth B, Chen C, Zhao Y, et al. Beta-amyloid oligomers induce tive damage: implications for the development and progression of phosphorylation of tau and inactivation of insulin receptor substrate via Alzheimer’s disease. J Neurochem. 2006;96(1):1–13. c-Jun N-terminal kinase signalling: suppression by omega-3 fatty acids 121. Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of and curcumin. J Neurosci. 2009;29(28):9078–89. 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxida- 100. Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tan- tion, in the brain in Mild Cognitive Impairment and early Alzheimer’s gles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. disease. Neurobiol Aging. 2006;27(8):1094–9. 2001;293(5534):1491–5. 122. Marmol F, Rodriguez CA, Sanchez J, Chamizo VD. Anti-oxidative 101. Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM. effects produced by environmental enrichment in the hip - Age-dependent induction of congophilic neurofibrillary tau inclusions pocampus and cerebral cortex of male and female rats. Brain Res. in tau transgenic mice. Am J Pathol. 2001;158(2):555–62. 2015;10(1613):120–9. Majd et al. BMC Neurosci (2015) 16:69 Page 11 of 13 123. Butterfield DA, Kanski J. Brain protein oxidation in age-related neuro - 148. Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. Dopamine-dependent degenerative disorders that are associated with aggregated proteins. neurotoxicity of alpha-synuclein: a mechanism for selective neurode- Mech Ageing Dev. 2001;122(9):945–62. generation in Parkinson disease. Nat Med. 2002;8(6):600–6. 124. Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in 149. Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Alzheimer’s disease. J Neurochem. 2000;75(1):436–9. Neurol. 1996;55(3):259–72. 125. Shringarpure R, Grune T, Davies KJ. Protein oxidation and 20S 150. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero proteasome-dependent proteolysis in mammalian cells. Cell Mol Life I, Vidal L, Hoenicka J, Rodriguez O, Atares B, et al. The new mutation, Sci. 2001;58(10):1442–50. E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. 126. Pratico D, Delanty N. Oxidative injury in diseases of the central nervous Ann Neurol. 2004;55(2):164–73. system: focus on Alzheimer’s disease. Am J Med. 2000;109(7):577–85. 151. George JM, Jin H, Woods WS, Clayton DF. Characterization of a novel 127. Broe GA, Grayson DA, Creasey HM, Waite LM, Casey BJ, Bennett HP, protein regulated during the critical period for song learning in the Brooks WS, Halliday GM. Anti-inflammatory drugs protect against zebra finch. Neuron. 1995;15(2):361–72. Alzheimer disease at low doses. Arch Neurol. 2000;57(11):1586–91. 152. Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Gold- 128. Wu Q, Combs C, Cannady SB, Geldmacher DS, Herrup K. Beta-amyloid stein JM, Soriano F, Seubert P, et al. Red blood cells are the major source activated microglia induce cell cycling and cell death in cultured corti- of alpha-synuclein in blood. Neurodegener Dis. 2008;5(2):55–9. cal neurons. Neurobiol Aging. 2000;21(6):797–806. 153. Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K. Demon- 129. Benveniste EN, Nguyen VT, O’Keefe GM. Immunological aspects stration of alpha-synuclein immunoreactivity in neuronal and glial of microglia: relevance to Alzheimer’s disease. Neurochem Int. cytoplasm in normal human brain tissue using proteinase K and formic 2001;39(5–6):381–91. acid pretreatment. Exp Neurol. 2002;176(1):98–104. 130. Szczepanik AM, Funes S, Petko W, Ringheim GE. IL-4, IL-10 and IL-13 154. Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P. Alpha- modulate A beta(1–42)-induced cytokine and chemokine production synuclein and Parkinson’s disease. FASEB J. 2004;18(6):617–26. in primary murine microglia and a human monocyte cell line. J Neuro- 155. Perrin RJ, Woods WS, Clayton DF, George JM. Interaction of human immunol. 2001;113(1):49–62. alpha-Synuclein and Parkinson’s disease variants with phospholip- 131. Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K. Cell mediators ids. Structural analysis using site-directed mutagenesis. J Biol Chem. of inflammation in the Alzheimer disease brain. Alzheimer Dis Assoc 2000;275(44):34393–8. Disord. 2000;14(Suppl 1):S47–53. 156. Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, 132. Raina AK, Zhu X, Rottkamp CA, Monteiro M, Takeda A, Smith MA. Cyclin’ Orrison B, Chen A, Ellis CE, Paylor R, et al. Synaptic vesicle deple- toward dementia: cell cycle abnormalities and abortive oncogenesis in tion correlates with attenuated synaptic responses to prolonged Alzheimer disease. J Neurosci Res. 2000;61(2):128–33. repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 133. Arendt T, Holzer M, Gartner U. Neuronal expression of cycline depend- 2002;22(20):8797–807. ent kinase inhibitors of the INK4 family in Alzheimer’s disease. J Neural 157. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Transm. 1998;105(8–9):949–60. Alpha-synuclein cooperates with CSPalpha in preventing neurodegen- 134. Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict eration. Cell. 2005;123(3):383–96. the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci. 158. Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, 1998;18(8):2801–7. Savalle M, Nemani V, Chaudhry FA, Edwards RH, et al. Alpha-synuclein 135. Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement overexpression in PC12 and chromaffin cells impairs catecholamine of cell cycle elements, cyclin-dependent kinases, pRb, and E2F × DP, release by interfering with a late step in exocytosis. J Neurosci. B-amyloid-induced neuronal death. J Biol Chem. 1999;274(27):19011–6. 2006;26(46):11915–22. 136. Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal 159. Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC. cell death in Alzheimer’s disease. J Neurosci. 2001;21(8):2661–8. Alpha-synuclein promotes SNARE-complex assembly in vivo and 137. Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle in vitro. Science. 2010;329(5999):1663–7. events at all stages of Alzheimer’s disease. J Neurosci. 2003;23(7):2557–63. 160. Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji 138. Raina AK, Monteiro MJ, McShea A, Smith MA. The role of cell H, Shinoda T, Hisanaga S, Ueda K. Tubulin seeds alpha-synuclein fibril cycle-mediated events in Alzheimer’s disease. Int J Exp Pathol. formation. J Biol Chem. 2002;277(3):2112–7. 1999;80(2):71–6. 161. Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada 139. Zhu X, Raina AK, Boux H, Simmons ZL, Takeda A, Smith MA. Activation A, Saito T, Kaji H, Yoshii M, et al. Demonstration of a role for alpha-synu- of oncogenic pathways in degenerating neurons in Alzheimer disease. clein as a functional microtubule-associated protein. J Alzheimers Dis. Int J Dev Neurosci. 2000;18(4–5):433–7. 2004;6(4):435–42 (discussion 443–439). 140. Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM, 162. Zhou RM, Huang YX, Li XL, Chen C, Shi Q, Wang GR, Tian C, Wang ZY, Canonico PL, Nicoletti F, Sortino MA. Mitotic signaling by beta-amyloid Jing YY, Gao C, et al. Molecular interaction of alpha-synuclein with causes neuronal death. FASEB J. 1999;13(15):2225–34. tubulin influences on the polymerization of microtubule in vitro and 141. Copani A, Uberti D, Sortino MA, Bruno V, Nicoletti F, Memo M. Activa- structure of microtubule in cells. Mol Biol Rep. 2010;37(7):3183–92. tion of cell-cycle-associated proteins in neuronal death: a mandatory or 163. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg dispensable path? Trends Neurosci. 2001;24(1):25–31. MS, Shen J, Takio K, Iwatsubo T. alpha-Synuclein is phosphorylated in 142. Majd S, Zarifkar A, Rastegar K, Takhshid MA. Different fibrillar Abeta 1-42 synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4. concentrations induce adult hippocampal neurons to reenter various 164. Uversky VN. Neuropathology, biochemistry, and biophysics of alpha- phases of the cell cycle. Brain Res. 2008;1218:224–9. synuclein aggregation. J Neurochem. 2007;103(1):17–37. 143. Zhang M, Li J, Chakrabarty P, Bu B, Vincent I. Cyclin-dependent kinase 165. Tenreiro S, Reimao-Pinto MM, Antas P, Rino J, Wawrzycka D, Macedo D, inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion Rosado-Ramos R, Amen T, Waiss M, Magalhaes F, et al. Phosphorylation formation, and motor defects in Niemann-Pick Type C mice. Am J modulates clearance of alpha-synuclein inclusions in a yeast model of Pathol. 2004;165(3):843–53. Parkinson’s disease. PLoS Genet. 2014;10:e1004302. 144. Majd S, Chegini F, Chataway T, Zhou XF, Gai W. Reciprocal induction 166. Mahul-Mellier AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, between alpha-synuclein and beta-amyloid in adult rat neurons. Neu- Lamontanara AJ, Bisquertt A, Eliezer D, Masliah E, et al. c-Abl phospho- rotox Res. 2013;23(1):69–78. rylates alpha-synuclein and regulates its degradation, implication for 145. Nagy Z. The last neuronal division: a unifying hypothesis for the patho- alpha-synuclein clearance and contribution to the pathogenesis of genesis of Alzheimer’s disease. J Cell Mol Med. 2005;9(3):531–41. Parkinson’s Disease. Hum Mol Genet. 2014;23(11):2858–79. 146. Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L. Autophagy in aging 167. Tamo W, Imaizumi T, Tanji K, Yoshida H, Mori F, Yoshimoto M, Takahashi and neurodegenerative diseases: implications for pathogenesis and H, Fukuda I, Wakabayashi K, Satoh K. Expression of alpha-synuclein, therapy. Neurobiol Aging. 2014;35:941–57. the precursor of non-amyloid beta component of Alzheimer’s 147. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. disease amyloid, in human cerebral blood vessels. Neurosci Lett. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40. 2002;326(1):5–8. Majd et al. BMC Neurosci (2015) 16:69 Page 12 of 13 168. Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman 189. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, BT, McLean PJ. Formation of toxic oligomeric alpha-synuclein species in Marsden CD. Alterations in glutathione levels in Parkinson’s disease and living cells. PLoS One. 2008;3(4):e1867. other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 169. Paik SR, Shin HJ, Lee JH, Chang CS, Kim J. Copper(II)-induced self- 1994;36(3):348–55. oligomerization of alpha-synuclein. Biochem J. 1999;340(Pt 3):821–8. 190. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD. 170. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E. Increased nigral iron content and alterations in other metal ions occur- Oxidative stress induces amyloid-like aggregate formation of NACP/ ring in brain in Parkinson’s disease. J Neurochem. 1989;52(6):1830–6. alpha-synuclein in vitro. Neuroreport. 1999;10(4):717–21. 191. Spina MB, Cohen G. Dopamine turnover and glutathione oxida- 171. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are devel- tion: implications for Parkinson disease. Proc Natl Acad Sci USA. opmentally expressed, and alpha-synuclein regulates the size of the 1989;86(4):1398–400. presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 192. Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, Wong J, 2000;20(9):3214–20. Takenouchi T, Hashimoto M, Masliah E. alpha-Synuclein promotes mito- 172. Zhu M, Li J, Fink AL. The association of alpha-synuclein with membranes chondrial deficit and oxidative stress. Am J Pathol. 2000;157(2):401–10. affects bilayer structure, stability, and fibril formation. J Biol Chem. 193. Li WW, Yang R, Guo JC, Ren HM, Zha XL, Cheng JS, Cai DF. Localization 2003;278(41):40186–97. of alpha-synuclein to mitochondria within midbrain of mice. Neurore- 173. Jo E, Darabie AA, Han K, Tandon A, Fraser PE, McLaurin J. alpha- port. 2007;18(15):1543–6. Synuclein-synaptosomal membrane interactions: implications for 194. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. Mitochon- fibrillogenesis. Eur J Biochem. 2004;271(15):3180–9. drial association of alpha-synuclein causes oxidative stress. Cell Mol Life 174. Scott D, Roy S. alpha-Synuclein inhibits intersynaptic vesicle Sci. 2008;65(7–8):1272–84. mobility and maintains recycling-pool homeostasis. J Neurosci. 195. Dryanovski D, Guzman J, Xie Z, Galteri D, Volpicelli-Daley L, Lee V, Miller 2012;32(30):10129–35. R, Schumacker P, Surmeier D. Calcium entry and α-synuclein inclusions 175. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, elevate dendritic mitochondrial oxidant stress in dopaminergic neu- Hyman BT, McLean PJ, Unni VK. Distinct roles in vivo for the ubiquitin- rons. J Neurosci. 2013;33(24):10154–64. proteasome system and the autophagy-lysosomal pathway in the 196. Zaltieri M, Longhena F, Pizzi M, Missale C, Spano P, Bellucci A. Mitochon- degradation of α- synuclein. J Neurosci. 2011;31:14508–20. drial Dysfunction and α-synuclein Synaptic Pathology in Parkinson’s 176. Pan PY, Yue Z. Genetic causes of Parkinson’s disease and their links Disease: Who’s on First. Parkinsons Dis. 2015;108029:1–10. to autophagy regulation. Parkinsonism Relat Disord. 2014;20(Suppl 197. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic 1):S154–7. program in cell-free extracts: requirement for dATP and cytochrome c. 177. Iwata A, Miura S, Kanazawa I, Sawada M, Nukina N. alpha-Synuclein Cell. 1996;86(1):147–57. forms a complex with transcription factor Elk-1. J Neurochem. 198. Thayanidhi N, Helm JR, Nycz DC, Bentley M, Liang Y, Hay JC. Alpha- 2001;77(1):239–52. synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in 178. Sidhu A, Wersinger C, Vernier P. Does alpha-synuclein modulate mammalian cells by antagonizing ER/Golgi SNAREs. Mol Biol Cell. dopaminergic synaptic content and tone at the synapse? FASEB J. 2010;21(11):1850–63. 2004;18(6):637–47. 199. Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK. 179. Iwata A, Maruyama M, Kanazawa I, Nukina N. alpha-Synuclein Accumulation of toxic alpha-synuclein oligomer within endoplas- affects the MAPK pathway and accelerates cell death. J Biol Chem. mic reticulum occurs in alpha-synucleinopathy in vivo. J Neurosci. 2001;276(48):45320–9. 2012;32(10):3301–5. 180. Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, 200. Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW, Johnson Nukina N. Alpha-synuclein degradation by serine protease neurosin: E, Smith L, Aoki KR, Dolly JO. Evaluation of the therapeutic usefulness of implication for pathogenesis of synucleinopathies. Hum Mol Genet. botulinum neurotoxin B, C1, E, and F compared with the long lasting 2003;12(20):2625–35. type A. Basis for distinct durations of inhibition of exocytosis in central 181. Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, neurons. J Biol Chem. 2003;278(2):1363–71. Flavell RA. JNK-mediated induction of cyclooxygenase 2 is required for 201. Chen L, Jin J, Davis J, Zhou Y, Wang Y, Liu J, Lockhart PJ, Zhang J. neurodegeneration in a mouse model of Parkinson’s disease. Proc Natl Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochem Acad Sci USA. 2004;101(2):665–70. Biophys Res Commun. 2007;356(3):548–53. 182. Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B. 202. Soper JH, Roy S, Stieber A, Lee E, Wilson RB, Trojanowski JQ, Burd CG, alpha-Synuclein shares physical and functional homology with 14-3-3 Lee VM. Alpha-synuclein-induced aggregation of cytoplasmic vesicles proteins. J Neurosci. 1999;19(14):5782–91. in Saccharomyces cerevisiae. Mol Biol Cell. 2008;19(3):1093–103. 183. Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson’s 203. Gosavi N, Lee HJ, Lee JS, Patel S, Lee SJ. Golgi fragmentation occurs in disease: proximal triggers, distal effectors, and final steps. Apoptosis. the cells with prefibrillar alpha-synuclein aggregates and precedes the 2009;14(4):478–500. formation of fibrillar inclusion. J Biol Chem. 2002;277(50):48984–92. 184. Karunakaran S, Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar 204. Lee HJ, Khoshaghideh F, Lee S, Lee SJ. Impairment of microtubule- S, Ravindranath V. Activation of apoptosis signal regulating kinase 1 dependent trafficking by overexpression of alpha-synuclein. Eur J (ASK1) and translocation of death-associated protein, Daxx, in sub- Neurosci. 2006;24(11):3153–62. stantia nigra pars compacta in a mouse model of Parkinson’s disease: 205. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, protection by alpha-lipoic acid. FASEB J. 2007;21(9):2226–36. Nicoll RA, Edwards RH. Increased expression of alpha-synuclein reduces 185. Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, neurotransmitter release by inhibiting synaptic vesicle reclustering after McGeer PL. Alpha-synuclein activates stress signalling protein kinases in endocytosis. Neuron. 2010;65(1):66–79. THP-1 cells and microglia. Neurobiol Aging. 2008;29(5):739–52. 206. Saha AR, Hill J, Utton MA, Asuni AA, Ackerley S, Grierson AJ, Miller CC, 186. Wilms H, Rosenstiel P, Romero-Ramos M, Arlt A, Schafer H, Seegert D, Davies AM, Buchman VL, Anderton BH, et al. Parkinson’s disease alpha- Kahle PJ, Odoy S, Claasen JH, Holzknecht C, et al. Suppression of MAP synuclein mutations exhibit defective axonal transport in cultured kinases inhibits microglial activation and attenuates neuronal cell death neurons. J Cell Sci. 2004;117(Pt 7):1017–24. induced by alpha-synuclein protofibrils. Int J Immunopathol Pharmacol. 207. Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, 2009;22(4):897–909. Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an 187. Camilleri A, Vassallo N. The centrality of mitochondria in the patho- unrecognized component of amyloid in Alzheimer disease. Proc Natl genesis and treatment of Parkinson’s disease. CNS Neurosci Ther. Acad Sci USA. 1993;90(23):11282–6. 2014;20(7):591–602. 208. Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, et al. 188. Eisbach SE, Outeiro TF. Alpha-synuclein and intracellular trafficking: Extensive nuclear localization of alpha-synuclein in normal rat brain impact on the spreading of Parkinson’s disease pathology. J Mol Med neurons revealed by a novel monoclonal antibody. Neuroscience. (Berl). 2013;91(6):693–703. 2007;145(2):539–55. Majd et al. BMC Neurosci (2015) 16:69 Page 13 of 13 209. Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, Allsop D, 211. Gallardo G, Schluter OM, Sudhof TC. A molecular pathway of neurode- Hassan AH, Jensen PH, El-Agnaf OM. Detection of elevated levels of generation linking alpha-synuclein to ApoE and Abeta peptides. Nat soluble alpha-synuclein oligomers in post-mortem brain extracts Neurosci. 2008;11(3):301–8. from patients with dementia with Lewy bodies. Brain. 2009;132(Pt 4):1093–101. 210. Yang Y, Varvel NH, Lamb BT, Herrup K. Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models. J Neurosci. 2006;26(3):775–84. Submit your next manuscript to BioMed Central and take full advantage of: Convenient online submission Thorough peer review No space constraints or color ﬁgure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Neuroscience Springer Journals http://www.deepdyve.com/lp/springer-journals/neuronal-response-in-alzheimer-s-and-parkinson-s-disease-the-effect-of-x2CL00ZLnc

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References (211)

A Giovanni, F Wirtz-Brugger, E Keramaris, R Slack, DS Park (1999)
Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F × DP, B-amyloid-induced neuronal death
J Biol Chem, 274
C Casas, N Sergeant, JM Itier, V Blanchard, O Wirths, N Kolk, V Vingtdeux, E Steeg, G Ret, T Canton (2004)
Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model
Am J Pathol, 165
JJ Pei, E Braak, H Braak, I Grundke-Iqbal, K Iqbal, B Winblad, RF Cowburn (1999)
Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes
J Neuropathol Exp Neurol, 58
T Sarajarvi, JT Tuusa, A Haapasalo, JJ Lackman, R Sormunen, S Helisalmi, JT Roehr, AR Parrado, P Makinen, L Bertram (2011)
Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking
Mol Cell Biol, 31
H Yamaguchi, K Ishiguro, T Uchida, A Takashima, CA Lemere, K Imahori (1996)
Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II
Acta Neuropathol, 92
DB Carter, E Dunn, DD McKinley, NC Stratman, TP Boyle, SL Kuiper, JA Oostveen, RJ Weaver, JA Boller, ME Gurney (2001)
Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain
Ann Neurol, 50
M Zhang, J Li, P Chakrabarty, B Bu, I Vincent (2004)
Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice
Am J Pathol, 165
A Iwata, M Maruyama, T Akagi, T Hashikawa, I Kanazawa, S Tsuji, N Nukina (2003)
Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies
Hum Mol Genet, 12
RS Jope, GV Johnson (2004)
The glamour and gloom of glycogen synthase kinase-3
Trends Biochem Sci, 29
R Tycko (2003)
Insights into the amyloid folding problem from solid-state NMR
Biochemistry, 42
S Chandra, G Gallardo, R Fernandez-Chacon, OM Schluter, TC Sudhof (2005)
Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration
Cell, 123
E Norrby (2011)
Prions and protein-folding diseases
J Intern Med, 270
M Zaltieri, F Longhena, M Pizzi, C Missale, P Spano, A Bellucci (2015)
Mitochondrial Dysfunction and α-synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First
Parkinsons Dis., 108029
I Ferrer, R Blanco, M Carmona, B Puig, M Barrachina, C Gomez, S Ambrosio (2001)
Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and Dementia with Lewy bodies
J Neural Transm, 108
W Tamo, T Imaizumi, K Tanji, H Yoshida, F Mori, M Yoshimoto, H Takahashi, I Fukuda, K Wakabayashi, K Satoh (2002)
Expression of alpha-synuclein, the precursor of non-amyloid beta component of Alzheimer’s disease amyloid, in human cerebral blood vessels
Neurosci Lett, 326
MA Alim, QL Ma, K Takeda, T Aizawa, M Matsubara, M Nakamura, A Asada, T Saito, H Kaji, M Yoshii (2004)
Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein
J Alzheimers Dis, 6
JJ Pei, H Braak, WL An, B Winblad, RF Cowburn, K Iqbal, I Grundke-Iqbal (2002)
Up- regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease
Brain Res Mol Brain Res, 109
J Busser, DS Geldmacher, K Herrup (1998)
Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain
J Neurosci, 18
N Gosavi, HJ Lee, JS Lee, S Patel, SJ Lee (2002)
Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion
J Biol Chem, 277
FM Laferla, KN Green, S Oddo (2007)
Intracellular amyloid-beta in Alzheimer’s disease
Nat Rev Neurosci, 8
PH Reddy (2006)
Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer’s disease
J Neurochem, 96
M Zhu, J Li, AL Fink (2003)
The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation
J Biol Chem, 278
GK Gouras, H Xu, JN Jovanovic, JD Buxbaum, R Wang, P Greengard, NR Relkin, S Gandy (1998)
Generation and regulation of beta-amyloid peptide variants by neurons
J Neurochem, 71
RS Jope, CJ Yuskaitis, E Beurel (2007)
Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics
Neurochem Res, 32
A Iwata, M Maruyama, I Kanazawa, N Nukina (2001)
alpha-Synuclein affects the MAPK pathway and accelerates cell death
J Biol Chem, 276
LJ Hsu, Y Sagara, A Arroyo, E Rockenstein, A Sisk, M Mallory, J Wong, T Takenouchi, M Hashimoto, E Masliah (2000)
alpha-Synuclein promotes mitochondrial deficit and oxidative stress
Am J Pathol, 157
A Abelein, B Bolognesi, CM Dobson, A Graslund, C Lendel (2012)
Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid beta self-assembly
Biochemistry, 51
Y Yang, NH Varvel, BT Lamb, K Herrup (2006)
Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models
J Neurosci, 26
C Hooper, R Killick, S Lovestone (2008)
The GSK3 hypothesis of Alzheimer’s disease
J Neurochem, 104
P Fernandez-Vizarra, AP Fernandez, S Castro-Blanco, J Serrano, ML Bentura, R Martinez-Murillo, A Martinez, J Rodrigo (2004)
Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer’s disease
Histol Histopathol, 19
KE Paleologou, CL Kragh, DM Mann, SA Salem, R Al-Shami, D Allsop, AH Hassan, PH Jensen, OM El-Agnaf (2009)
Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies
Brain, 132
A Ho, TC Sudhof (2004)
Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage
Proc Natl Acad Sci USA, 101
M Stefani (2004)
Protein misfolding and aggregation: new examples in medicine and biology of the dark side of the protein world
Biochim Biophys Acta, 1739
JH Soper, S Roy, A Stieber, E Lee, RB Wilson, JQ Trojanowski, CG Burd, VM Lee (2008)
Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae
Mol Biol Cell, 19
K Imahori, T Uchida (1997)
Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease
J Biochem, 121
E Jo, AA Darabie, K Han, A Tandon, PE Fraser, J McLaurin (2004)
alpha-Synuclein-synaptosomal membrane interactions: implications for fibrillogenesis
Eur J Biochem, 271
J Gotz, F Chen, J Dorpe, RM Nitsch (2001)
Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils
Science, 293
M UamekKozio, W Furmaga-Jaboska, S Januszewski, J Brzozowska, M Scilewska, M Jaboski, R Pluta (2013)
Neuronal autophagy: self-eating or self-cannibalism in Alzheimer’s disease
Neurochem Res, 38
JD Smith (2000)
Apolipoprotein E4: an allele associated with many diseases
Ann Med, 32
A Klegeris, S Pelech, BI Giasson, J Maguire, H Zhang, EG McGeer, PL McGeer (2008)
Alpha-synuclein activates stress signalling protein kinases in THP-1 cells and microglia
Neurobiol Aging, 29
E Mandelkow, YH Song, O Schweers, A Marx, EM Mandelkow (1995)
On the structure of microtubules, tau, and paired helical filaments
Neurobiol Aging, 16
K Yamamoto, H Shimada, H Koh, S Ataka, T Miki (2014)
Serum levels of albumin-amyloid beta complexes are decreased in Alzheimer’s disease
Geriatr Gerontol Int, 14
J Xu, SY Kao, FJ Lee, W Song, LW Jin, BA Yankner (2002)
Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease
Nat Med, 8
MB Borgia, A Borgia, RB Best, A Steward, D Nettels, B Wunderlich, B Schuler, J Clarke (2011)
Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins
Nature, 474
M Torok, S Milton, R Kayed, P Wu, T McIntire, CG Glabe, R Langen (2002)
Structural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils studied by site-directed spin labeling
J Biol Chem, 277
J Burre, M Sharma, T Tsetsenis, V Buchman, MR Etherton, TC Sudhof (2010)
Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro
Science, 329
N Dragicevic, M Mamcarz, Y Zhu, R Buzzeo, J Tan, GW Arendash, PC Bradshaw (2010)
Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer’s transgenic mice
J Alzheimers Dis, 20
JN Keller, KB Hanni, WR Markesbery (2000)
Impaired proteasome function in Alzheimer’s disease
J Neurochem, 75
F Mori, K Tanji, M Yoshimoto, H Takahashi, K Wakabayashi (2002)
Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment
Exp Neurol, 176
CC Tan, JT Yu, MS Tan, T Jiang, XC Zhu, L Tan (2014)
Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy
Neurobiol Aging, 35
J Sian, DT Dexter, AJ Lees, S Daniel, Y Agid, F Javoy-Agid, P Jenner, CD Marsden (1994)
Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia
Ann Neurol, 36
VN Uversky (2003)
Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go?
Cell Mol Life Sci, 60
MH Magdesian, MM Carvalho, FA Mendes, LM Saraiva, MA Juliano, L Juliano, J Garcia-Abreu, ST Ferreira (2008)
Amyloid-beta binds to the extracellular cysteine- rich domain of Frizzled and inhibits Wnt/beta-catenin signaling
J Biol Chem, 283
S Tenreiro, MM Reimao-Pinto, P Antas, J Rino, D Wawrzycka, D Macedo, R Rosado-Ramos, T Amen, M Waiss, F Magalhaes (2014)
Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson’s disease
PLoS Genet., 10
D Dryanovski, J Guzman, Z Xie, D Galteri, L Volpicelli-Daley, V Lee, R Miller, P Schumacker, D Surmeier (2013)
Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons
J Neurosci, 33
RR Kopito, D Ron (2000)
Conformational disease
Nat Cell Biol, 2
M Hoshi, A Takashima, K Noguchi, M Murayama, M Sato, S Kondo, Y Saitoh, K Ishiguro, T Hoshino, K Imahori (1996)
Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain
Proc Natl Acad Sci USA, 93
S Majd, F Chegini, T Chataway, XF Zhou, W Gai (2013)
Reciprocal induction between alpha-synuclein and beta-amyloid in adult rat neurons
Neurotox Res, 23
S Sudoh, Y Kawamura, S Sato, R Wang, TC Saido, F Oyama, Y Sakaki, H Komano, K Yanagisawa (1998)
Presenilin 1 mutations linked to familial Alzheimer’s disease increase the intracellular levels of amyloid beta-protein 1-42 and its N-terminally truncated variant(s) which are generated at distinct sites
J Neurochem, 71
AL Mahul-Mellier, B Fauvet, A Gysbers, I Dikiy, A Oueslati, S Georgeon, AJ Lamontanara, A Bisquertt, D Eliezer, E Masliah (2014)
c-Abl phosphorylates alpha-synuclein and regulates its degradation, implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson’s Disease
Hum Mol Genet, 23
LS Forno (1996)
Neuropathology of Parkinson’s disease
J Neuropathol Exp Neurol, 55
A Copani, D Uberti, MA Sortino, V Bruno, F Nicoletti, M Memo (2001)
Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?
Trends Neurosci, 24
J Nunan, DH Small (2000)
Regulation of APP cleavage by alpha-, beta- and gamma- secretases
FEBS Lett, 483
TL Benzinger, DM Gregory, TS Burkoth, H Miller-Auer, DG Lynn, RE Botto, SC Meredith (1998)
Propagating structure of Alzheimer’s beta-amyloid(10-35) is parallel beta-sheet with residues in exact register
Proc Natl Acad Sci USA, 95
K Takuma, F Fang, W Zhang, S Yan, E Fukuzaki, H Du, A Sosunov, G McKhann, Y Funatsu, N Nakamichi (2009)
RAGE-mediated signalling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction
Proc Natl Acad Sci USA, 106
S Karunakaran, L Diwakar, U Saeed, V Agarwal, S Ramakrishnan, S Iyengar, V Ravindranath (2007)
Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson’s disease: protection by alpha-lipoic acid
FASEB J, 21
K Ueda, H Fukushima, E Masliah, Y Xia, A Iwai, M Yoshimoto, DA Otero, J Kondo, Y Ihara, T Saitoh (1993)
Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease
Proc Natl Acad Sci USA, 90
A Lloret, T Fuchsberger, E Giraldo, J Vina (2015)
Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer’s disease
Free Radic Biol Med, 83
R Shringarpure, T Grune, KJ Davies (2001)
Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells
Cell Mol Life Sci, 58
X Alvira-Botero, R Perez-Gonzalez, C Spuch, T Vargas, D Antequera, M Garzon, F Bermejo-Pareja, E Carro (2010)
Megalin interacts with APP and the intracellular adapter protein FE65 in neurons
Mol Cell Neurosci, 45
J Yuan, BA Yankner (2000)
Apoptosis in the nervous system
Nature, 407
E Storey, R Cappai (1999)
The amyloid precursor protein of Alzheimer’s disease and the Abeta peptide
Neuropathol Appl Neurobiol, 25
Q Wu, C Combs, SB Cannady, DS Geldmacher, K Herrup (2000)
Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons
Neurobiol Aging, 21
Y Yang, DS Geldmacher, K Herrup (2001)
DNA replication precedes neuronal cell death in Alzheimer’s disease
J Neurosci, 21
R Barbour, K Kling, JP Anderson, K Banducci, T Cole, L Diep, M Fox, JM Goldstein, F Soriano, P Seubert (2008)
Red blood cells are the major source of alpha-synuclein in blood
Neurodegener Dis, 5
LM Fleming, KH Weisgraber, WJ Strittmatter, JC Troncoso, GV Johnson (1996)
Differential binding of apolipoprotein E isoforms to tau and other cytoskeletal proteins
Exp Neurol, 138
SE Eisbach, TF Outeiro (2013)
Alpha-synuclein and intracellular trafficking: impact on the spreading of Parkinson’s disease pathology
J Mol Med (Berl), 91
X Wang, T Huang, G Bu, H Xu (2014)
Dysregulation of protein trafficking in neurodegeneration
Mol Neurodegenr., 9
RM Zhou, YX Huang, XL Li, C Chen, Q Shi, GR Wang, C Tian, ZY Wang, YY Jing, C Gao (2010)
Molecular interaction of alpha-synuclein with tubulin influences on the polymerization of microtubule in vitro and structure of microtubule in cells
Mol Biol Rep, 37
A Sidhu, C Wersinger, P Vernier (2004)
Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse?
FASEB J, 18
I Ferrer, R Blanco, M Carmona, B Puig (2001)
Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress- activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies
J Neural Transm, 108
JQ Trojanowski, M Mawal-Dewan, ML Schmidt, J Martin, VM Lee (1993)
Localization of the mitogen activated protein kinase ERK2 in Alzheimer’s disease neurofibrillary tangles and senile plaque neurites
Brain Res, 618
MG Spillantini, ML Schmidt, VM Lee, JQ Trojanowski, R Jakes, M Goedert (1997)
Alpha-synuclein in Lewy bodies
Nature, 388
T Wisniewski, B Frangione (1992)
Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid
Neurosci Lett, 135
A Mudher, S Lovestone (2002)
Alzheimer’s disease-do tauists and baptists finally shake hands?
Trends Neurosci, 25
A Recchia, P Debetto, A Negro, D Guidolin, SD Skaper, P Giusti (2004)
Alpha-synuclein and Parkinson’s disease
FASEB J, 18
Y Yang, EJ Mufson, K Herrup (2003)
Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease
J Neurosci, 23
K Iqbal, AC Alonso, CX Gong, S Khatoon, JJ Pei, JZ Wang, I Grundke-Iqbal (1998)
Mechanisms of neurofibrillary degeneration and the formation of neurofibrillary tangles
J Neural Transm Suppl, 53
DD Murphy, SM Rueter, JQ Trojanowski, VM Lee (2000)
Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons
J Neurosci, 20
EN Benveniste, VT Nguyen, GM O’Keefe (2001)
Immunological aspects of microglia: relevance to Alzheimer’s disease
Neurochem Int, 39
OA Levy, C Malagelada, LA Greene (2009)
Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps
Apoptosis, 14
MJ Ladu, C Reardon, L Eldik, AM Fagan, G Bu, D Holtzman, GS Getz (2000)
Lipoproteins in the central nervous system
Ann N Y Acad Sci, 903
M DiCiero Miranda, VM de Bruin, MR Vale, GS Viana (2000)
Lipid peroxidation and nitrite plus nitrate levels in brain tissue from patients with Alzheimer’s disease
Gerontology, 46
SM Son, ES Jung, HJ Shin, J Byun, I Mook-Jung (2012)
Aβ-induced formation of autophagosomes is mediated by RAGECaMKK β-AMPK signaling
Neurobiol Aging, 33
GA Broe, DA Grayson, HM Creasey, LM Waite, BJ Casey, HP Bennett, WS Brooks, GM Halliday (2000)
Anti-inflammatory drugs protect against Alzheimer disease at low doses
Arch Neurol, 57
A Camilleri, N Vassallo (2014)
The centrality of mitochondria in the pathogenesis and treatment of Parkinson’s disease
CNS Neurosci Ther., 20
H Fujiwara, M Hasegawa, N Dohmae, A Kawashima, E Masliah, MS Goldberg, J Shen, K Takio, T Iwatsubo (2002)
alpha-Synuclein is phosphorylated in synucleinopathy lesions
Nat Cell Biol, 4
L Chen, J Jin, J Davis, Y Zhou, Y Wang, J Liu, PJ Lockhart, J Zhang (2007)
Oligomeric alpha-synuclein inhibits tubulin polymerization
Biochem Biophys Res Commun, 356
VN Uversky (2007)
Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation
J Neurochem, 103
KE Larsen, Y Schmitz, MD Troyer, E Mosharov, P Dietrich, AZ Quazi, M Savalle, V Nemani, FA Chaudhry, RH Edwards (2006)
Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis
J Neurosci, 26
VM Nemani, W Lu, V Berge, K Nakamura, B Onoa, MK Lee, FA Chaudhry, RA Nicoll, RH Edwards (2010)
Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis
Neuron, 65
HW Klafki, M Staufenbiel, J Kornhuber, J Wiltfang (2006)
Therapeutic approaches to Alzheimer’s disease
Brain, 129
MA Alim, MS Hossain, K Arima, K Takeda, Y Izumiyama, M Nakamura, H Kaji, T Shinoda, S Hisanaga, K Ueda (2002)
Tubulin seeds alpha-synuclein fibril formation
J Biol Chem, 277
AM Blokhuis, EJ Groen, M Koppers, LH Berg, RJ Pasterkamp (2013)
Protein aggregation in amyotrophic lateral sclerosis
Acta Neuropathol, 125
DG Cook, MS Forman, JC Sung, S Leight, DL Kolson, T Iwatsubo, VM Lee, RW Doms (1997)
Alzheimer’s Abeta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells
Nat Med, 3
A Copani, F Condorelli, A Caruso, C Vancheri, A Sala, AM Giuffrida Stella, PL Canonico, F Nicoletti, MA Sortino (1999)
Mitotic signaling by beta-amyloid causes neuronal death
FASEB J, 13
A Iwata, S Miura, I Kanazawa, M Sawada, N Nukina (2001)
alpha-Synuclein forms a complex with transcription factor Elk-1
J Neurochem, 77
S Miranda, C Opazo, LF Larrondo, FJ Munoz, F Ruiz, F Leighton, NC Inestrosa (2000)
The role of oxidative stress in the toxicity induced by amyloid beta-peptide in Alzheimer’s disease
Prog Neurobiol, 62
JP Brion (1998)
Neurofibrillary tangles and Alzheimer’s disease
Eur Neurol, 40
A Kakizuka (1998)
Protein precipitation: a common etiology in neuro-degenerative disorders?
Trends Genet, 14
PY Pan, Z Yue (2014)
Genetic causes of Parkinson’s disease and their links to autophagy regulation
Parkinsonism Relat Disord., 20
PP Roux, J Blenis (2004)
ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions
Microbiol Mol Biol Rev, 68
MB Spina, G Cohen (1989)
Dopamine turnover and glutathione oxidation: implications for Parkinson disease
Proc Natl Acad Sci USA, 86
D Schubert, A Klar, M Park, R Dargusch, WH Fischer (2006)
F-spondin promotes nerve precursor differentiation
J Neurochem, 96
JT Huse, RW Doms (2000)
Closing in on the amyloid cascade: recent insights into the cell biology of Alzheimer’s disease
Mol Neurobiol, 22
M Townsend, T Mehta, DJ Selkoe (2007)
Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway
J Biol Chem, 282
T Harada, T Morooka, S Ogawa, E Nishida (2001)
ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1
Nat Cell Biol, 3
G Gallardo, OM Schluter, TC Sudhof (2008)
A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides
Nat Neurosci, 11
F Marmol, CA Rodriguez, J Sanchez, VD Chamizo (2015)
Anti-oxidative effects produced by environmental enrichment in the hippocampus and cerebral cortex of male and female rats
Brain Res, 10
J Yan, XH Liu, MZ Han, YM Wang, XL Sun, N Yu, T Li, B Su, ZY Chen (2015)
Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer’s disease
Neurobiol Aging., 36
E Masliah, A Sisk, M Mallory, L Mucke, D Schenk, D Games (1996)
Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer’s disease
J Neurosci, 16
M Pende, SH Um, V Mieulet, M Sticker, VL Goss, J Mestan, M Mueller, S Fumagalli, SC Kozma, G Thomas (2004)
S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway
Mol Cell Biol, 24
TI Williams, BC Lynn, WR Markesbery, MA Lovell (2006)
Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease
Neurobiol Aging, 27
AR Saha, J Hill, MA Utton, AA Asuni, S Ackerley, AJ Grierson, CC Miller, AM Davies, VL Buchman, BH Anderton (2004)
Parkinson’s disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons
J Cell Sci, 117
S Ly, R Altman, J Petrlova, Y Lin, S Hilt, T Huser, TA Laurence, JC Voss (2013)
Binding of apolipoprotein E inhibits the oligomer growth of amyloid-beta peptide in solution as determined by fluorescence cross-correlation spectroscopy
J Biol Chem, 288
LL Versen, RJ Mortishire-Smith, SJ Pollack, MS Shearman (1995)
The toxicity in vitro of beta-amyloid protein
Biochem J, 311
CG Almeida, RH Takahashi, GK Gouras (2006)
Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system
J Neurosci, 26
C Spuch, S Ortolano, C Navarro (2012)
New insights in the amyloid-Beta interaction with mitochondria
J Aging Res, 2012
DA Butterfield, S Griffin, G Munch, GM Pasinetti (2002)
Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer’s disease brain exists
J Alzheimers Dis, 4
S Majd, A Zarifkar, K Rastegar, MA Takhshid (2008)
Different fibrillar Abeta 1-42 concentrations induce adult hippocampal neurons to reenter various phases of the cell cycle
Brain Res, 1218
DA Butterfield (2002)
Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review
Free Radic Res, 36
DJ Selkoe (2000)
Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein
Ann N Y Acad Sci, 924
H Braak, K Del Tredici (2004)
Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-beta formation
Neurobiol Aging, 25
JJ Lucas, F Hernandez, P Gomez-Ramos, MA Moran, R Hen, J Avila (2001)
Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice
EMBO J, 20
DE Cabin, K Shimazu, D Murphy, NB Cole, W Gottschalk, KL McIlwain, B Orrison, A Chen, CE Ellis, R Paylor (2002)
Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein
J Neurosci, 22
E Colla, PH Jensen, O Pletnikova, JC Troncoso, C Glabe, MK Lee (2012)
Accumulation of toxic alpha-synuclein oligomer within endoplasmic reticulum occurs in alpha-synucleinopathy in vivo
J Neurosci, 32
M Stefani, S Rigacci (2013)
Protein folding and aggregation into amyloid: the interference by natural phenolic compounds
Int J Mol Sci, 14
QL Ma, F Yang, ER Rosario, OJ Ubeda, W Beech, DJ Gant, PP Chen, B Hudspeth, C Chen, Y Zhao (2009)
Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signalling: suppression by omega-3 fatty acids and curcumin
J Neurosci, 29
H Wilms, P Rosenstiel, M Romero-Ramos, A Arlt, H Schafer, D Seegert, PJ Kahle, S Odoy, JH Claasen, C Holzknecht (2009)
Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils
Int J Immunopathol Pharmacol, 22
PG Foran, N Mohammed, GO Lisk, S Nagwaney, GW Lawrence, E Johnson, L Smith, KR Aoki, JO Dolly (2003)
Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons
J Biol Chem, 278
A Kamal, GB Stokin, Z Yang, CH Xia, LS Goldstein (2000)
Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I
Neuron, 28
RJ Perrin, WS Woods, DF Clayton, JM George (2000)
Interaction of human alpha-Synuclein and Parkinson’s disease variants with phospholipids. Structural analysis using site-directed mutagenesis
J Biol Chem, 275
R Gomez-Sintes, F Hernandez, JJ Lucas, J Avila (2011)
GSK-3 mouse models to study neuronal apoptosis and neurodegeneration
Front Mol Neurosci, 4
AM Wertkin, RS Turner, SJ Pleasure, TE Golde, SG Younkin, JQ Trojanowski, VM Lee (1993)
Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta- amyloid or A4 peptides
Proc Natl Acad Sci USA, 90
X Liu, CN Kim, J Yang, R Jemmerson, X Wang (1996)
Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c
Cell, 86
J Olah, O Vincze, D Virok, D Simon, Z Bozso, N Tokesi, I Horvath, E Hlavanda, J Kovacs, A Magyar (2011)
Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein
J Biol Chem, 286
A Brown (2003)
Axonal transport of membranous and nonmembranous cargoes: a unified perspective
J Cell Biol, 160
Q Liu, CV Zerbinatti, J Zhang, HS Hoe, B Wang, SL Cole, J Herz, L Muglia, G Bu (2007)
Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1
Neuron, 56
KF Winklhofer, J Tatzelt, C Haass (2008)
The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases
EMBO J, 27
SR Paik, HJ Shin, JH Lee, CS Chang, J Kim (1999)
Copper(II)-induced self-oligomerization of alpha-synuclein
Biochem J, 340
AG Henriques, SI Vieira, ESEF Cruz, ESOA Cruz (2010)
Abeta promotes Alzheimer’s disease-like cytoskeleton abnormalities with consequences to APP processing in neurons
J Neurochem, 113
AM Szczepanik, S Funes, W Petko, GE Ringheim (2001)
IL-4, IL-10 and IL-13 modulate A beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line
J Neuroimmunol, 113
KS Kosik, H Shimura (2005)
Phosphorylated tau and the neurodegenerative foldopathies
Biochim Biophys Acta, 1739
AK Raina, MJ Monteiro, A McShea, MA Smith (1999)
The role of cell cycle-mediated events in Alzheimer’s disease
Int J Exp Pathol, 80
DA Butterfield, J Kanski (2001)
Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins
Mech Ageing Dev, 122
J Davis-Salinas, SM Saporito-Irwin, CW Cotman, WE Nostrand (1995)
Amyloid beta-protein induces its own production in cultured degenerating cerebrovascular smooth muscle cells
J Neurochem, 65
V Echeverria, A Ducatenzeiler, E Dowd, J Janne, SM Grant, M Szyf, F Wandosell, J Avila, H Grimm, SB Dunnett (2004)
Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons
Neuroscience, 129
WW Li, R Yang, JC Guo, HM Ren, XL Zha, JS Cheng, DF Cai (2007)
Localization of alpha-synuclein to mitochondria within midbrain of mice
Neuroreport, 18
J Espana, L Gimenez-Llort, J Valero, A Minano, A Rabano, J Rodriguez-Alvarez, FM LaFerla, CA Saura (2010)
Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice
Biol Psychiatry, 67
AM Saunders (2000)
Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses
J Neuropathol Exp Neurol, 59
H Akiyama, T Arai, H Kondo, E Tanno, C Haga, K Ikeda (2000)
Cell mediators of inflammation in the Alzheimer disease brain
Alzheimer Dis Assoc Disord, 14
C Spuch, S Ortolano, C Navarro (2012)
LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer’s disease
Front Physiol, 3
E Masliah, RD Terry, RM DeTeresa, LA Hansen (1989)
Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease
Neurosci Lett, 103
MS Parihar, A Parihar, M Fujita, M Hashimoto, P Ghafourifar (2008)
Mitochondrial association of alpha-synuclein causes oxidative stress
Cell Mol Life Sci, 65
TC Dickson, CE King, GH McCormack, JC Vickers (1999)
Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease
Exp Neurol, 156
JM George, H Jin, WS Woods, DF Clayton (1995)
Characterization of a novel protein regulated during the critical period for song learning in the zebra finch
Neuron, 15
R Castellani, K Hirai, G Aliev, KL Drew, A Nunomura, A Takeda, AD Cash, ME Obrenovich, G Perry, MA Smith (2002)
Role of mitochondrial dysfunction in Alzheimer’s disease
J Neurosci Res, 70
JJ Zarranz, J Alegre, JC Gomez-Esteban, E Lezcano, R Ros, I Ampuero, L Vidal, J Hoenicka, O Rodriguez, B Atares (2004)
The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia
Ann Neurol, 55
DR Howlett, DL Simmons, C Dingwall, G Christie (2000)
In search of an enzyme: the beta-secretase of Alzheimer’s disease is an aspartic proteinase
Trends Neurosci, 23
MS Parihar, T Hemnani (2004)
Alzheimer’s disease pathogenesis and therapeutic interventions
J Clin Neurosci, 11
J Lewis, DW Dickson, WL Lin, L Chisholm, A Corral, G Jones, SH Yen, N Sahara, L Skipper, D Yager (2001)
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Science, 293
N Ostrerova, L Petrucelli, M Farrer, N Mehta, P Choi, J Hardy, B Wolozin (1999)
alpha-Synuclein shares physical and functional homology with 14-3-3 proteins
J Neurosci, 19
P Kettunen, S Larsson, S Holmgren, S Olsson, L Minthon, H Zetterberg, K Blennow, S Nilsson, A Sjölander (2015)
Genetic variants of GSK3B are associated with biomarkers for Alzheimer’s disease and cognitive function
J Alzheimers Dis, 44
KH Cho, DM Durbin, A Jonas (2001)
Role of individual amino acids of apolipoprotein A-I in the activation of lecithin: cholesterol acyltransferase and in HDL rearrangements
J Lipid Res, 42
T Hansen, JF Rehfeld, FC Nielsen (2004)
GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding
NeuroReport, 15
DT Dexter, FR Wells, AJ Lees, F Agid, Y Agid, P Jenner, CD Marsden (1989)
Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease
J Neurochem, 52
TF Outeiro, P Putcha, JE Tetzlaff, R Spoelgen, M Koker, F Carvalho, BT Hyman, PJ McLean (2008)
Formation of toxic oligomeric alpha-synuclein species in living cells
PLoS One, 3
H Oakley, SL Cole, S Logan, E Maus, P Shao, J Craft, A Guillozet-Bongaarts, M Ohno, J Disterhoft, L Eldik (2006)
Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation
J Neurosci, 26
TA Bayer, O Wirths, K Majtenyi, T Hartmann, G Multhaup, K Beyreuther, C Czech (2001)
Key factors in Alzheimer’s disease: beta-amyloid precursor protein processing, metabolism and intraneuronal transport
Brain Pathol, 11
DT Loo, A Copani, CJ Pike, ER Whittemore, AJ Walencewicz, CW Cotman (1993)
Apoptosis is induced by beta-amyloid in cultured central nervous system neurons
Proc Natl Acad Sci USA, 90
JC Wiley, M Hudson, KC Kanning, LC Schecterson, M Bothwell (2005)
Familial Alzheimer’s disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment
J Neurochem, 94
AK Raina, X Zhu, CA Rottkamp, M Monteiro, A Takeda, MA Smith (2000)
Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease
J Neurosci Res, 61
PT Lansbury (1997)
Structural neurology: are seeds at the root of neuronal degeneration?
Neuron, 19
K Spittaels, C Haute, J Dorpe, H Geerts, M Mercken, K Bruynseels, R Lasrado, K Vandezande, I Laenen, T Boon (2000)
Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice
J Biol Chem, 275
HJ Lee, F Khoshaghideh, S Lee, SJ Lee (2006)
Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein
Eur J Neurosci, 24
Z Nagy (2005)
The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer’s disease
J Cell Mol Med, 9
SL Lambourne, LA Sellers, TG Bush, SK Choudhury, PC Emson, YH Suh, LS Wilkinson (2005)
Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer’s disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities
Mol Cell Biol, 25
D Scott, S Roy (2012)
alpha-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis
J Neurosci, 32
JC Vickers, TC Dickson, PA Adlard, HL Saunders, CE King, G McCormack (2000)
The cause of neuronal degeneration in Alzheimer’s disease
Prog Neurobiol, 60
X Zhu, AK Raina, H Boux, ZL Simmons, A Takeda, MA Smith (2000)
Activation of oncogenic pathways in degenerating neurons in Alzheimer disease
Int J Dev Neurosci, 18
DP Karpinar, MB Balija, S Kugler, F Opazo, N Rezaei-Ghaleh, N Wender, HY Kim, G Taschenberger, BH Falkenburger, H Heise (2009)
Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models
EMBO J, 28
D Ebrahimi-Fakhari, I Cantuti-Castelvetri, Z Fan, E Rockenstein, E Masliah, BT Hyman, PJ McLean, VK Unni (2011)
Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α- synuclein
J Neurosci, 31
S Kumar, O Wirths, S Theil, J Gerth, TA Bayer, J Walter (2013)
Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer’s disease
Acta Neuropathol, 125
T Ishihara, B Zhang, M Higuchi, Y Yoshiyama, JQ Trojanowski, VM Lee (2001)
Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice
Am J Pathol, 158
HK Anandatheerthavarada, G Biswas, MA Robin, NG Avadhani (2003)
Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells
J Cell Biol, 161
S Hunot, M Vila, P Teismann, RJ Davis, EC Hirsch, S Przedborski, P Rakic, RA Flavell (2004)
JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson’s disease
Proc Natl Acad Sci USA, 101
N Thayanidhi, JR Helm, DC Nycz, M Bentley, Y Liang, JC Hay (2010)
Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs
Mol Biol Cell, 21
S Majd, K Rastegar, A Zarifkar, MA Takhshid (2007)
Fibrillar beta-amyloid (Abeta) (1-42) elevates extracellular Abeta in cultured hippocampal neurons of adult rats
Brain Res, 1185
D Pratico, N Delanty (2000)
Oxidative injury in diseases of the central nervous system: focus on Alzheimer’s disease
Am J Med, 109
M Takami, Y Nagashima, Y Sano, S Ishihara, M Morishima-Kawashima, S Funamoto, Y Ihara (2009)
gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment
J Neurosci, 29
J Nah, J Yuan, YK Jung (2015)
Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach
Mol Cells, 38
S Varadarajan, S Yatin, M Aksenova, DA Butterfield (2000)
Review: Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity
J Struct Biol, 130
T Arendt, M Holzer, U Gartner (1998)
Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer’s disease
J Neural Transm, 105
JP Greenfield, J Tsai, GK Gouras, B Hai, G Thinakaran, F Checler, SS Sisodia, P Greengard, H Xu (1999)
Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides
Proc Natl Acad Sci USA, 96
M Sunde, CC Blake (1998)
From the globular to the fibrous state: protein structure and structural conversion in amyloid formation
Q Rev Biophys, 31
M Hashimoto, LJ Hsu, Y Xia, A Takeda, A Sisk, M Sundsmo, E Masliah (1999)
Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro
Neuroreport, 10
A Schneider, L Rajendran, M Honsho, M Gralle, G Donnert, F Wouters, SW Hell, M Simons (2008)
Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons
J Neurosci, 28
RH Takahashi, TA Milner, F Li, EE Nam, MA Edgar, H Yamaguchi, MF Beal, H Xu, P Greengard, GK Gouras (2002)
Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology
Am J Pathol, 161
FG Felice, PT Velasco, MP Lambert, K Viola, SJ Fernandez, ST Ferreira, WL Klein (2002)
Abeta oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine
J Biol Chem, 282
S Yu, X Li, G Liu, J Han, C Zhang, Y Li, S Xu, C Liu, Y Gao, H Yang (2007)
Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody
Neuroscience, 145
K Yanagisawa (2002)
Role of gangliosides in Alzheimer’s disease
Biochim Biophys Acta, 1768

Publisher: Springer Journals
Copyright: Copyright © 2015 by Majd et al.
Subject: Biomedicine; Neurosciences; Neurobiology; Animal Models
eISSN: 1471-2202
DOI: 10.1186/s12868-015-0211-1
pmid: 26499115
Publisher site: See Article on Publisher Site

Abstract

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deteriora- tion and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed. Keywords: Alzheimer’s disease, Parkinson’s disease, Beta-amyloid, Alpha-synuclein, Intracellular signalling, Neurotoxicity, Neurodegeneration Pathophysiology of toxic proteins Background All the proteins implicated in neurodegenerative diseases Protein misfolding and aggregation contribute to the share the common pattern of dysfunctional structure pathophysiology of neurodegenerative disorders such as due to an unusual folding [5–7]. Through folding, pro - Alzheimer’s (AD) and Parkinson’s diseases (PD). In physi- teins acquire the three dimensional structures required ological situations protein misfolding is sensed by the cel- to undertake their biological functions. This process is lular control systems as a threat which is then followed prone to errors, causing the protein not to acheive its by an immediate response. Any delay detecting the mis- functional structure, building a toxic protein deposition. folded proteins, may result in damage and progression of When an aggregation status is established, disaggregation neurodegenerative disorders [1, 2]. Unfortunately, not all rarely occurs because under physiological conditions, the cellular responses to misfolded proteins are neuro- the equilibrium is in favour of aggregation [8–11]. These protective. Activation of some intracellular pathways as a early aggregates are believed to be the source of toxicity part of this response occasionally create further damage, in neurodegenerative disorders. interruption in synaptic connections and neuronal apop- tosis [3, 4]. Alzheimer’s disease (AD) AD is the most common form of dementia and among the leading causes of death in adults. AD is associ- *Correspondence: shohreh.majd@flinders.edu.au Centre for Neuroscience and Paramedic Unit, School of Medicine, ated with two main lesions: extracellular plaques made Flinders University of South Australia, Adelaide, SA 5042, Australia of beta-amyloid (Aβ) and intracellular neurofibrillary Full list of author information is available at the end of the article © 2015 Majd et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Majd et al. BMC Neurosci (2015) 16:69 Page 2 of 13 tangles (NFT) made of tau protein [12, 13]. The plaques was obtained for both Aβ 1-40 and 1–42, two of the most are the consequences of abnormal protein folding and toxic forms of amyloid protein [35, 36]. aggregation with direct and indirect toxic effects on neu - Aβ oligomers can be generated both extra- and intra- ronal survival [14, 15]. cellularly. Extracellular Aβ toxicity could be mediated through binding to receptors such as NMDA and dis- Aβ biochemical structure and toxicity rupting the calcium balance of the neuron [37, 38]. Extra- Aβ, the principle protein implicated in development of cellular Aβ is internalized, stored in the lysosomes and AD, is derived from amyloid precursor protein (APP). can leak into the cytosol by destabilization of the lyso- More than ten isoforms of the protein are characterized some membrane. Aβ oligomers have the ability to inhibit by different lengths of amino acid chains, and among the function of proteasomes causing neuronal apopto- them APP695 is exclusively expressed in neurons. The sis [39, 40]. Toxicity of fibrillar and oligomers of Aβ also transmembrane region of APP is placed near the c-termi- occurs through cytoskeletal disruption, tangle develop- nus, and contains a Kunitz-type protease inhibitor (KPI) ment, loss of synapses and inhibition of hippocampal domain, which acts as a potent inhibitor of coagulation long-term potentiation (LTP). This is the so-called “Aβ factors IXa and XIa, however, APP695 lacks the KPI cascade theory” of AD [12, 41, 42]. domain [16, 17]. Intracellular inclusions of Aβ have been found within APP can act as a receptor for a signalling glycoprotein neuronal compartments. [43, 44]. Internalization of F-spondin that is released by neurons and possesses roles Aβ occurs either via binding to low-density lipopro- in axonal guidance, neuronal differentiation and neuro- tein related protein-2 (LRP2) [45], LRP-1 [46, 47] or to repair [18, 19]. Some other functions of APP have also a receptor for advanced glycation end-product (RAGE) been proposed, including serving as a link between kine- [48]. The presence of Aβ in various subcellular com - sin and synaptic vesicles being an adhesion protein, a role partments, suggests different sites for APP proteolysis, in metal ion homeostasis, neuroprotection and a func- such as Aβ40 in the trans-Golgi network and Aβ42 in tion relating to promotion of neurite growth [16, 20]. the endoplasmic reticulum (ER) [49, 50] as well as Golgi APP is degraded in lysosomes [21–23] (Fig. 1). Aβ is compartments [51]. Autophagic vacuoles enriched with produced when a normal cleavage of APP occurs α and β presenilin-1 (PS1), APP and Aβ are found frequently in secretase cleave APP, outside the membrane. Also three degenerating neurons in patients with AD. This suggests members of a family of peptidase proteins, ADAM, (a an essential role for autophagy in clearing the aggregated disintegrin and metalloproteinase) have a recognized peptide through a lysosomal-dependent pathway [52]. role cleaving the extracellular portion of APP, in the same Aβ disrupts APP trafficking, and initiates a pathological way that α-secretase does [24]. Proteolysis of APP by cascade of Aβ accumulation [39, 43]. An accumulation of β-secretase cleaves APP695 after Met-596 and produces vacuoles filled with Aβ occurs as a result of interruption a large soluble N-terminal (sAPPβ) and a small mem- to neuronal trafficking associated with the disruption of brane-bound C-terminal fragment (C99), sAPPβ, is neu- autopghgosomes [53]. Aβ itself is also able to activate the roprotective and regulates synaptic plasticity. This larger adenosine monophosphate kinase (AMPK) pathway, gen- fragment of APP can also act as a microtubule associated erating more autophagic vacuoles [54]. Thus, AD patients protein (MAP) [25]. appear to produce abundant extracellular Aβ, resulting APP can undergo proteolysis at the cell surface. Its C99 in plaque formation with a high level of toxicity causing fragment can be processed by γ- secretase, presenilin 1 extensive neuronal apoptosis [55–57]. and 2, γ-secretase produces Aβ isoforms of 1-40, 1-42 or 1-43 [17, 26–28]. These peptides are made throughout Aß and kinases life, but in AD they accumulate due to either increased Glycogen synthase kinase‑3 beta (GSK‑3β) production or decreased degradation or removal. Glycogen synthase kinase-3 beta (GSK-3β) is well-known Remaining Aβ has the potential to enhance its own pro- for its role in glycogen metabolism, activation of tran- duction in cerebrovascular smooth muscles and hip- scription factors and phosphorylation of tau. GSK3 is pocampal neurons [29, 30]. Excess peptides, particular modulated through a variety of pathways including wnt, those of Aβ 1-40, 1-42 and 1-43, form toxic aggregates, phosphatidylinositide-3 kinase (PI3K) and Akt deacti- which result in progression of AD [16, 31, 32]. vate GSK-3β by phosphorylating Ser9 [58, 59], increasing Filaments of amyloid structure are approximately GSK-3β, in pre-tangles which is closely associated with 10 nm wide and 0.1–10 μm long with a β-sheet struc- tangle-bearing neurons suggesting a role in tau hyper- ture in their motif [33, 34]. Using Electron Paramagnetic phosphorylation in AD [60–64]. A recent report associ- Resonance Spectroscopy (EPRS) the β-sheet structure ated GSK-3β gene variants with the level of tau and Aβ42 Majd et al. BMC Neurosci (2015) 16:69 Page 3 of 13 Fig. 1 Cellular trafficking of APP and Aβ. APP cleavage to peptides occurs both in lysosomes after its endocytosis and at the surface of cell mem- brane. The proteolysis products accumulate intracellularly or are released into extracellular space in cerebrospinal fluid in AD as well as cognitive function pathway [74, 75]. MAPKs are a family of serine/threo- [65]. Further in vivo evidence of GSK-3β’s role in AD has nine kinases that contribute to the hyperprocessing of come from transgenic mouse models over-expressing this APP and hyper-phosphorylation of tau associated with kinase with a presentation of tau hyper-phosphorylation, AD [76, 77]. MAPKs phosphorylate proteins with regula- astrocytosis, and neuronal death [66, 67]. The concurrent tory functions including other kinases, transcription fac- hyper-phosphorylation of other cellular structures such tors and enzymes [78–80]. Stimulation of MAPK by Aβ as presinilines, β-catenin and GSK3-cAMP responsive in a Ras-dependent manner, leads to tau phosphorylation element-binding protein also produces some of the path- [81–84]. It has also been demonstrated that activation of ological features of AD [61, 68, 69]. MAPK by neurotrophins as well as Aβ induces p35, the Aβ exposure induces GSK-3β activity, extensive phos- specific activator of cyclin dependent kinase 5 (cdk5) in phorylation of tau and cell death. Aβ inhibits PI3K and the cell cycle. Thus another means of damaging the neu - Akt pathways and inactivates the wnt cascade,. Because ron through MAPK activation by Aβ could be re-activa- these pathways eventually deactivate GSK3, their inhibi- tion of the cell cycle, which is considered a lethal event tion will result in hyperactivity of GSK3 [70, 71] (Fig. 2). for neurons [78–85]. This Aβ-induced GSK-3β hyperactivity triggers the mito - chondrial fragmentation leading to neuronal apoptosis Aß, cytoskeleton and axonal transport [72]. GSK-3β also interacts with pyruvate dehydrogenase A constant interaction between microtubules and MAPs (PDH), thereby reducing levels of acetyl-CoA [73]. such as tau is a necessary element for axonal transport [86]. Tau holds the microtubular tracks in place and plays Mitogen‑activated protein kinases (MAPK) a key role in their stability [87]. When tau is subjected Aβ affects another intracellular second messenger the to hyper-phosphorylation, it loses the ability to bind to extracellular signal regulated Kinase (ERK)/MAPK microtubules and to maintain their structure, causing tau Majd et al. BMC Neurosci (2015) 16:69 Page 4 of 13 Fig. 2 Aβ and GSK3. Aβ binding to membrane receptors such as insulin receptor (IR) inhibits the activity of Akt and wnt through PI3K inhibition. Inactivation of Akt and wnt consequently dephosphorylate GSK3 which causes tau hyper-phosphorylation and microtubular disorganisation aggregation into paired helical filaments (PHF) and NFTs Aβ and apolipoprotein E (apoE) [88]. The number of NFTs is linked to the degree of demen - ApoE is a normal constituent of cells. In the nervous tia, suggesting a correlation between NFT, dystrophic neu- system, it acts as the main lipid transport protein with a rite formation and neuronal dysfunction [89–91]. It seems wide variety of roles in intracellular signalling, immune that interrupting axonal transport will interrupt neuronal modulation, glucose metabolism, lipid movement and function and lead to eventual death [92–94]. lipoprotein metabolism [102]. ApoE has been detected in Deposition of Aβ plaques precedes tau phosphoryla- the amyloid plaques in AD [103]. tion and exerts a damaging effect upon the cytoskeleton The ability of ApoE to interact with Aβ, demonstrated giving rise to PHF formation. [41]. Intraneuronal for- its critical role in amyloid deposition and clearance [91, mation of Aβ also happens prior to appearance of PHF, 102, 104]. The apoE4 allele of ApoE is associated with making it the upstream step in triggering the neurode- high cholesterol in cardiovascular disease and particu- generative events [95, 96]. larly AD, however, the apoE2 allele confers some protec- Further evidence that Aβ formation precedes PHF for- tion against hypercholesterolemia [102, 105, 106]. ApoE2 mation comes from a tau mutation study when tau muta- and E3 formed stable complexes with Aβ at levels of 20 tion produced tau-inclusion tangles but not plaques, fold greater than those occurring with apoE4 [107]. The however, APP or presenilin mutations caused both greater affinity of ApoE2 and E3 for Aβ protects neurons plaques and tangles. Transgenic mice doubly mutant for from neurotoxic effects of Aβ by facilitating the uptake mutant APP and tau have more tangles than mice with of these complexes by apoE receptors. Conversely, apoE4 the single mutant tau transgene [97, 98]. Tau phospho- accelerates Aβ deposition and progression/growth of Aβ rylation occurs through activation of c-Jun N-terminal seeds to larger Aβ plaques [108, 109]. kinase (JNK), a member of MAPK [99]. In a study, amy- loid injections exacerbated tangle pathology in mutant- Aβ, mitochondria and oxidative stress tau mice but why Aβ injections did not stimulate tau The central role of Aβ isoforms, in elevating free radi - pathology with wild-type tau is not known [100], when cal levels and oxidative stress led to the introduction of other transgenic mice overexpressing wild-type tau an Aβ-oxidative stress model for neurotoxicity in AD exhibited tangles [101]. [110–112]. Majd et al. BMC Neurosci (2015) 16:69 Page 5 of 13 Post-mortem studies revealed a wide range of [126]. Oxidative stress also elicits an inflammatory Aβ-derived mitochondrial dysfunction in AD patients response [127] through microglial activation [128, 129] [113–115]. Intracellular Aβ can be localized to mito- and release of pro inflammatory cytokines [130], promot - chondrial membranes, where it interrupts the normal ing inflammation and invasion of Aβ plaques by astro - mitochondrial function through blocking mitochondrial cytes [131] which mature plaques into neuritic plaques, a channels and inhibiting mitochondrial protein activ- common finding in AD patients. ity. By blocking the electron transport chain, Aβ accu- mulation leads to an increase in reactive oxygen species Aβ and cell cycle (ROS), causing oxidative stress [114, 116–118] (Fig. 3) Inappropriate cell cycle activation is an early event seen which leads to a deregulation of the ROS signalling path- in AD brains [132]. Although adult neurons are con- way in AD [119]. Superoxide radicals, produced due to sidered to be in a terminally-differentiated state, accu - mitochondrial dysfunction oxidate different neuronal mulation of associated cell cycle-related proteins have compartments such as proteins, lipids and DNA [117, been described in degenerating neurons [133–137]. It 120]. The evidence of oxidative damage in patients with is assumed that ectopic localization of cyclins, cyclin- mild cognitive dementia (MCD) shows that the oxida- dependent kinases (cdks) and cdk inhibitors are the tion insult occurs as one of the first steps of AD [121]. results of abortive attempt by neurons to re-enter the cell Chronic oxidative stress inhibits tau dephosphorylation cycle. Re-entering the cell cycle is a consequence of mito- by inhibiting tau phosphatase as well as increasing the gen factors and perhaps is promoted by the recruitment phosphorylation of tau by activating p38 [119]. of mitogenic signal transduction mechanisms [138, 139]. The other aspect of oxidative stress relates to pro - Subjecting neurons to Aβ, forces the cell to re-enter the tein oxidation. Oxidative modification of proteins is cell cycle, cross the G1/S phase transition and begin de important in aging and age-related neurodegenerative novo DNA synthesis before apoptotic death occurs [140– disorders [122]. Protein oxidation results in protein dys- 142], this could be inhibited by cell-cycle inhibitors [143, function associated with conformational changes. The 144]. These findings led to the hypothesis that vulner - oxidized protein may also have a higher resistance to pro- able neurons re-enter the cell cycle and proceed through teolysis and protein cross-linking and aggregation will be S phase, but then abort somatic division and eventually increased [123]. The aggregated misfolded proteins then degenerate [145]. get trapped in proteasome’s pore leading to proteasomal dysfunction [124, 125]. A vicious cycle of misfolded pro- Parkinson’s disease (PD) tein accumulation is then established. Parkinson’s disease (PD) is the second most common Aggregated peptides have the potential to initiate oxi- neurodegenerative disorder among the adults. The pro - dative stress through cellular dysfunction leading to cal- gressive impaired motor function in patients with PD is cium accumulation and increased tau polymerization an outcome of dopaminergic neuronal loss particularly in the substantia nigra (SN) [146]. A common finding from degenerating dopaminergic cells includes intracellular inclusions of particles, known as Lewy bodies (LBs) [147, 148]. The major component of LBs is the fibrillar form of α-Syn and this suggests the role of protein misfolding in Parkinson’s pathology [149, 150]. α‑Synuclein structure and toxicity α-Syn is an acidic synaptic protein (14 kDa), which is expressed in a wide range of tissues including the brain [151–153]. α-Syn retains the ability of building a β-sheet structure after prolonged incubation due to its posses- sion of a hydrophobic region of amino acids from 66 to 95 [154]. As a vesicle associated protein, the main func- Fig. 3 Aβ and mitochondrial dysfunction. Attachment of Aβ to inner tions of α-Syn are regulating membrane stability, neu- membrane of mitochondria alters the different aspects of mitochon- ronal plasticity, synaptic rearrangement, controlling drial activity. Blocking electron chain through reducing complex IV activity, damaging mitochondrial DNA (mtDNA), inhibiting tricarbo- vesicular trafficking and neurotransmission through a xylic acid ( TCA) cycle and ATP production, enhancing cytochrome chaperon-like function to other proteins [134, 155–159]. c release and activation of apoptotic pathways, and increasing the Due to the ability α-Syn to interact with tubulin, α-Syn mitochondria production of ROS are some of the examples also shows a microtubule-associated activity [160–162]. Majd et al. BMC Neurosci (2015) 16:69 Page 6 of 13 Lesions from autopsied PD brains show a marked decreased MTT levels, reduction of glutathione and high increase in S129 hyperphosphorylated α-Syn [163] which levels of iron, in brain tissue confirmed the presence of creates high molecular weight α-Syn with a high poten- oxidative stress as a common finding in PD [189–193] 2+ tial for self-assembly. This makes it a likely candidate to Oxidative stress affects the Ca shift and balance in be a toxic protein in the event of aggregation [164, 165]. cytoplasm, leading to stimulation of mitochondrial nitric α-Syn could also be phosphorylated on Tyr39 with no oxide synthase (mtNOS) [194, 195]. α-Syn also has the link between this phosphorylation and pathological fea- ability of binding to pro apoptotic protein BAD, a mem- tures [166]. ber of Bcl-2 family [182]. As the result of this attachment, Fibrillar α-Syn as the main component of LBs, is pre- Bcl-2 protein is removed from mitochondrial pores, sent in many dying cells in PD [167], however, oligomeric allowing cytochrome c to be released from the mito- α-Syn also possesses enough toxicity to damage neu- chondria. This event triggers neuronal apoptosis dem - rons [168]. The process of misfolding of α-Syn has been onstrating a link between mitochondrial dysfunction and shown to be accelerated by many metals such as copper synaptic accumulation of α-Syn in PD [195, 196]. [169] and ferric ion and also by elevated intracellular cytochrome c [170]. Conformational changes leads to α‑Synuclein and axonal trafficking protein misfolding reduce the ability of α-Syn to inter- α-Syn ability to act as a MAP, allows microtubules to act with the vesicular trafficking and modulating neuro - maintain their stability, to carry cargos in an energy- transmission [171–174]. Conformational changes and dependent manner, and to facilitate neurotransmitter consequent aggregation α-Syn also triggers a cascade of release [159, 161]. Overexpression and phosporylation neuronal response such as autophagy, one of the main of α-Syn, however, affects the normal function of ER pathways of α-Syn degradation [175, 176]. and Golgi system. α-Syn directly binds to ER and the Golgi apparatus and inhibits the soluble NSF attach- α‑Synuclein and MAPK ment protein receptor (SNARE) complex assembly [197, Regulation of MAPK pathway is a downstream effect of 198]. The SNARE complex is made of vesicular SNARE α-Syn. In neurons, α-Syn binding to MAPK inhibits this proteins (v-SNARE) and target membrane SNARE pro- pathway. In particular, α-Syn binds directly to ERK2 and teins (t-SNARE). It possesses the ability of self-assembly indirectly to Elk-1, which is also an ERK2 substrate [177]. and allows vesicular fusion to cell membrane [199, 200]. u Th s α-Syn reduces dopamine transporter (DAT) inser - Blocking this assembly by α-Syn overexpression inter- tion in the synaptic membranes of axonal terminals [178]. feres with neurotransmitter release and reuptake (Fig. 4). α-Syn also decreases MAPK activation through reducing Consequently, relocating cellular proteins within the cell the phosphorylation of p38 and down regulating c-fos or from the cell toward the membrane and eventual neu- gene [179, 180]. rotransmission will be disturbed [201]. The eventual out - Phosphorylation and accumulation of MAPK elements come would include protein accumulation inside the cell, have been reported in PD patients [81, 172]. One of the Golgi system fragmentation, a decrease in neurotrans- MAPK elements is JNK, that is phosphorylated in PD and mitter release and neuronal apoptosis [202–204]. α-Syn activates the transcription factor of c-jun. Activation of also reduces polymerization of tubulin. Whether reduc- c-jun increases the level of cell death genes expression in ing polymerization of tubulin is a direct outcome or an dopaminergic neurons [82, 181]. JNK also inhibits Bcl-2 indirect one, through generating mitochondrial dysfunc- survival protein by activation of pro-apoptotic proteins tion and lack of ATP for polymerization, the outcome of Bad and Bim [182, 183]. The misregulation of MAPK represents itself as a disrupted axonal transport and neu- eventually leads to neuronal apoptosis. Inhibiting JNK rite degeneration [20, 203, 205]. phosphorylation, however, can protect neurons from death [184]. Activation of ERK has also been reported in α‑Syn and Aβ interaction glial cells which consequently starts a cascade of inflam - Both AD and PD show similar clinical presentations in matory responses and blocking that pathway reduces their mid to late stages [206, 207] suggesting the possibil- microglial activation [185, 186]. ity of interaction between α-Syn and Aβ [25, 144, 208]. It has been shown that instead of immediate cell death, α‑Synuclein and oxidative stress affected neurons live for several months in a near- func - α-Syn overexpression causes the impairment of mito- tional state [209, 210]. Constant production of both pro- chondrial homeostasis [187] leading to oxidative stress teins allows continuing protein–protein interaction and and dopamine oxidation [188]. Formation of giant as a result, a reciprocal induction between α-Syn and Aβ mitochondria and laminated bodies, autophagozomes, could cause a gradual increase in the protein levels of Majd et al. BMC Neurosci (2015) 16:69 Page 7 of 13 Fig. 4 α-Syn in normal condition binds to synaptic vesicle membrane and also v-SNARE. v-SNARE assembly to t-SNARE creates SNARE complex and results in synaptic vesicle fusion to cell membrane and neurotransmitter release. α-Syn clusters synaptic vesicles in the axonal terminal and produces a high concentration of presynaptic vesicles at a certain area of plasma membrane. Vesicular α-Syn also binds to early endosomes and facilitates neurotransmitter refilling of vesicles. α-Syn accumulation/fibrilation inhibits vesicular refilling, blocks SNARE complex formation and reduces the number of docking neurotransmitter vesicles Abbreviations both types, before neurodegeneration commences [144]. Aβ: beta-amyloid; AD: Alzheimer’s disease; apoE: apolipoprotein E; APP: amy- The PI3K pathway and ApoE could contribute to this loid precursor protein; α-Syn: alpha-synuclein; cdk: cyclin dependent kinase; interaction, as manipulation of PI3K reduced the recipro- ER: endoplasmic reticulum; ERK: extracellular signal regulated kinase; GSK-3β: glycogen synthase kinase-3 Beta; JNK: Jun N-terminal kinase; KPI: Kunitz-type cal elevation of α-Syn and Aβ [144]. Deletion of ApoE in protease inhibitor; LBs: Lewy bodies; LRP2: low-density lipoprotein related pro- α-Syn transgenic mice decreased the levels of Aβ, thereby tein-2; LTP: long-term potentiation; MAPK: mitogen-activated protein kinases; alleviating the onset of disease [211]. More research is mtNOS: mitochondrial nitric oxide synthase; NFT: neurofibrillary tangles; NGF: nerve growth factor; PD: Parkinson’s disease; PDH: pyruvate dehydrogenase; still required to achieve a complete understanding of the PHF: paired helical filaments; PI3K: phosphatidylinositide-3kinase; RAGE: glyca- underlying mechanisms. tion end-product; ROS: reactive oxygen species; SN: substantia nigra; SNARE: NSF attachment protein receptor; t-SNARE: target membrane SNARE protein; v-SNARE: vesicular SNARE protein. Conclusion Although the process of neuronal death is a common Authors’ contributions feature in AD and PD, the underlying mechanisms are SM, HG and JP conceived and drafted the manuscript. All authors read and approved the final manuscript. still under investigation. Some aspects of toxicity may be specific for a distinct type of neurodegenerative disorder Author details however common cellular mechanisms with a substan- Centre for Neuroscience and Paramedic Unit, School of Medicine, Flinders University of South Australia, Adelaide, SA 5042, Australia. Department tial overlap underlie the neuronal responses to the toxic of Human Physiology, School of Medicine, Flinders University of South Aus- proteins. tralia, Adelaide, SA 5042, Australia. In conclusion, neuronal death in neurodegenera- Acknowledgements tive disorders is not a single-cause event and establish- SM was a member of Alzheimer’s and Parkinson’s lab at Flinders University of ing the exact links between the activation mechanisms South Australia when she started writing the manuscript and we would like to in response to toxic proteins could open a window for thank the lab members for their enthusiastic discussions about protein toxicity in neurodegenerative disorders. promising therapeutic interventions. Majd et al. BMC Neurosci (2015) 16:69 Page 8 of 13 Competing interests 21. Gouras GK, Xu H, Jovanovic JN, Buxbaum JD, Wang R, Greengard P, The authors declare that they have no competing interests. Relkin NR, Gandy S. Generation and regulation of beta-amyloid peptide variants by neurons. J Neurochem. 1998;71(5):1920–5. Received: 12 January 2015 Accepted: 13 October 2015 22. Schneider A, Rajendran L, Honsho M, Gralle M, Donnert G, Wouters F, Hell SW, Simons M. Flotillin-dependent clustering of the amyloid pre- cursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci. 2008;28(11):2874–82. 23. Sarajarvi T, Tuusa JT, Haapasalo A, Lackman JJ, Sormunen R, Helisalmi S, Roehr JT, Parrado AR, Makinen P, Bertram L, et al. Cysteine 27 vari- References ant of the delta-opioid receptor affects amyloid precursor protein 1. Uversky VN. Protein folding revisited. A polypeptide chain at the processing through altered endocytic trafficking. Mol Cell Biol. folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol 2011;31(11):2326–40. Life Sci. 2003;60(9):1852–71. 24. Wang X, Huang T, Bu G, Xu H. Dysregulation of protein trafficking in 2. Stefani M, Rigacci S. Protein folding and aggregation into amyloid: neurodegeneration. Mol Neurodegenr. 2014;9(31):1–9. the interference by natural phenolic compounds. Int J Mol Sci. 25. Olah J, Vincze O, Virok D, Simon D, Bozso Z, Tokesi N, Horvath I, Hla- 2013;14(6):12411–57. vanda E, Kovacs J, Magyar A, et al. Interactions of pathological hallmark 3. Kakizuka A. Protein precipitation: a common etiology in neuro-degen- proteins: tubulin polymerization promoting protein/p25, beta-amyloid, erative disorders? Trends Genet. 1998;14(10):396–402. and alpha-synuclein. J Biol Chem. 2011;286(39):34088–100. 4. Kopito RR, Ron D. Conformational disease. Nat Cell Biol. 26. Howlett DR, Simmons DL, Dingwall C, Christie G. In search of an 2000;2(11):E207–9. enzyme: the beta-secretase of Alzheimer’s disease is an aspartic pro- 5. Karpinar DP, Balija MB, Kugler S, Opazo F, Rezaei-Ghaleh N, Wender N, teinase. Trends Neurosci. 2000;23(11):565–70. Kim HY, Taschenberger G, Falkenburger BH, Heise H, et al. Pre-fibrillar 27. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, alpha-synuclein variants with impaired beta-structure increase neuro- Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and toxicity in Parkinson’s disease models. EMBO J. 2009;28(20):3256–68. tetrapeptide release from the transmembrane domain of beta-carboxyl 6. Borgia MB, Borgia A, Best RB, Steward A, Nettels D, Wunderlich B, terminal fragment. J Neurosci. 2009;29(41):13042–52. Schuler B, Clarke J. Single-molecule fluorescence reveals sequence-spe - 28. Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M. Familial cific misfolding in multidomain proteins. Nature. 2011;474(7353):662–5. Alzheimer’s disease mutations inhibit gamma-secretase-mediated lib- 7. Norrby E. Prions and protein-folding diseases. J Intern Med. eration of beta-amyloid precursor protein carboxy-terminal fragment. J 2011;270(1):1–14. Neurochem. 2005;94(5):1189–201. 8. Stefani M. Protein misfolding and aggregation: new examples in medi- 29. Davis-Salinas J, Saporito-Irwin SM, Cotman CW, Van Nostrand WE. cine and biology of the dark side of the protein world. Biochim Biophys Amyloid beta-protein induces its own production in cultured Acta. 2004;1739(1):5–25. degenerating cerebrovascular smooth muscle cells. J Neurochem. 9. Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding: 1995;65(2):931–4. gain- and loss-of-function in neurodegenerative diseases. EMBO J. 30. Majd S, Rastegar K, Zarifkar A, Takhshid MA. Fibrillar beta-amyloid 2008;27(2):336–49. (Abeta) (1-42) elevates extracellular Abeta in cultured hippocampal 10. Abelein A, Bolognesi B, Dobson CM, Graslund A, Lendel C. Hydropho- neurons of adult rats. Brain Res. 2007;1185:321–7. bicity and conformational change as mechanistic determinants for 31. Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, nonspecific modulators of amyloid beta self-assembly. Biochemistry. Vingtdeux V, van de Steeg E, Ret G, Canton T, et al. Massive CA1/2 2012;51(1):126–37. neuronal loss with intraneuronal and N-terminal truncated Abeta42 11. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. accumulation in a novel Alzheimer transgenic model. Am J Pathol. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2004;165(4):1289–300. 2013;125(6):777–94. 32. Yamamoto K, Shimada H, Koh H, Ataka S, Miki T. Serum levels of 12. Selkoe DJ. Toward a comprehensive theory for Alzheimer’s disease. albumin-amyloid beta complexes are decreased in Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumula- Geriatr Gerontol Int. 2014;14(3):716–23. tion and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 33. Sunde M, Blake CC. From the globular to the fibrous state: protein struc- 2000;924:17–25. ture and structural conversion in amyloid formation. Q Rev Biophys. 13. Kumar S, Wirths O, Theil S, Gerth J, Bayer TA, Walter J. Early intraneu- 1998;31:1–39. ronal accumulation and increased aggregation of phosphorylated 34. Benzinger TL, Gregory DM, Burkoth TS, Miller-Auer H, Lynn DG, Botto RE, Abeta in a mouse model of Alzheimer’s disease. Acta Neuropathol. Meredith SC. Propagating structure of Alzheimer’s beta-amyloid(10-35) 2013;125(5):699–709. is parallel beta-sheet with residues in exact register. Proc Natl Acad Sci 14. Lansbury PT Jr. Structural neurology: are seeds at the root of neuronal USA. 1998;95:13407–12. degeneration? Neuron. 1997;19(6):1151–4. 35. Tycko R. Insights into the amyloid folding problem from solid-state 15. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts NMR. Biochemistry. 2003;42:3151–9. A, Ohno M, Disterhoft J, Van Eldik L, et al. Intraneuronal beta-amyloid 36. Torok M, Milton S, Kayed R, Wu P, McIntire T, Glabe CG, Langen R. Struc- aggregates, neurodegeneration, and neuron loss in transgenic mice tural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils with five familial Alzheimer’s disease mutations: potential factors in studied by site-directed spin labeling. J Biol Chem. 2002;277:40810–5. amyloid plaque formation. J Neurosci. 2006;26(40):10129–40. 37. Yanagisawa K. Role of gangliosides in Alzheimer’s disease. Biochim 16. Storey E, Cappai R. The amyloid precursor protein of Alzheimer’s disease Biophys Acta. 2002;1768:1943–51. and the Abeta peptide. Neuropathol Appl Neurobiol. 1999;25(2):81–97. 38. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, 17. Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta- and Klein WL. Abeta oligomers induce neuronal oxidative stress through an gamma- secretases. FEBS Lett. 2000;483(1):6–10. N-methyl-d -aspartate receptor-dependent mechanism that is blocked 18. Ho A, Sudhof TC. Binding of F-spondin to amyloid-beta precursor by the Alzheimer drug memantine. J Biol Chem. 2002;282:11590–601. protein: a candidate amyloid-beta precursor protein ligand that modu- 39. Laferla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer’s lates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci USA. disease. Nat Rev Neurosci. 2007;8:499–509. 2004;101(8):2548–53. 40. Almeida CG, Takahashi RH, Gouras GK. Beta-amyloid accumulation 19. Schubert D, Klar A, Park M, Dargusch R, Fischer WH. F-spondin promotes impairs multivesicular body sorting by inhibiting the ubiquitin-proteas- nerve precursor differentiation. J Neurochem. 2006;96(2):444–53. ome system. J Neurosci. 2006;26:4277–88. 20. Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS. Axonal transport of 41. Huse JT, Doms RW. Closing in on the amyloid cascade: recent amyloid precursor protein is mediated by direct binding to the kinesin insights into the cell biology of Alzheimer’s disease. Mol Neurobiol. light chain subunit of kinesin-I. Neuron. 2000;28(2):449–59. 2000;22(1–3):81–98. Majd et al. BMC Neurosci (2015) 16:69 Page 9 of 13 42. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic brains staged for Alzheimer disease neurofibrillary changes. J Neuro - approaches to Alzheimer’s disease. Brain. 2006;129(Pt 11):2840–55. pathol Exp Neurol. 1999;58(9):1010–9. 43. Wertkin AM, Turner RS, Pleasure SJ, Golde TE, Younkin SG, Trojanowski 64. Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K. JQ, Lee VM. Human neurons derived from a teratocarcinoma cell line Preferential labeling of Alzheimer neurofibrillary tangles with antisera express solely the 695-amino acid amyloid precursor protein and pro- for tau protein kinase ( TPK) I/glycogen synthase kinase-3 beta and duce intracellular beta- amyloid or A4 peptides. Proc Natl Acad Sci USA. cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol. 1993;90(20):9513–7. 1996;92(3):232–41. 44. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal 65. Kettunen P, Larsson S, Holmgren S, Olsson S, Minthon L, Zetterberg H, MF, Xu H, Greengard P, Gouras GK. Intraneuronal Alzheimer abeta42 Blennow K, Nilsson S, Sjölander A. Genetic variants of GSK3B are associ- accumulates in multivesicular bodies and is associated with synaptic ated with biomarkers for Alzheimer’s disease and cognitive function. J pathology. Am J Pathol. 2002;161(5):1869–79. Alzheimers Dis. 2015;44(4):1313–22. 45. Alvira-Botero X, Perez-Gonzalez R, Spuch C, Vargas T, Antequera D, 66. Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Garzon M, Bermejo-Pareja F, Carro E. Megalin interacts with APP and Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, et al. Glycogen the intracellular adapter protein FE65 in neurons. Mol Cell Neurosci. synthase kinase-3beta phosphorylates protein tau and rescues the 2010;45(3):306–15. axonopathy in the central nervous system of human four-repeat tau 46. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, transgenic mice. J Biol Chem. 2000;275(52):41340–9. Bu G. Amyloid precursor protein regulates brain apolipoprotein E and 67. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. cholesterol metabolism through lipoprotein receptor LRP1. Neuron. Decreased nuclear beta-catenin, tau hyperphosphorylation and 2007;56(1):66–78. neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 47. Spuch C, Ortolano S, Navarro C. LRP-1 and LRP-2 receptors function 2001;20(1–2):27–39. in the membrane neuron. Trafficking mechanisms and proteolytic 68. Hansen T, Rehfeld JF, Nielsen FC. GSK-3beta reduces cAMP-induced processing in Alzheimer’s disease. Front Physiol. 2012;3:269. cholecystokinin gene expression by inhibiting CREB binding. NeuroRe- 48. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, port. 2004;15(5):841–5. McKhann G, Funatsu Y, Nakamichi N, et al. RAGE-mediated signalling 69. Jope RS, Yuskaitis CJ, Beurel E. Glycogen synthase kinase-3 (GSK3): contributes to intraneuronal transport of amyloid-beta and neuronal inflammation, diseases, and therapeutics. Neurochem Res. dysfunction. Proc Natl Acad Sci USA. 2009;106(47):20021–6. 2007;32(4–5):577–95. 49. Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee 70. Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal VM, Doms RW. Alzheimer’s Abeta(1-42) is generated in the endoplas- transduction cascades common to the insulin receptor pathway. J Biol mic reticulum/intermediate compartment of NT2N cells. Nat Med. Chem. 2007;282(46):33305–12. 1997;3(9):1021–3. 71. Magdesian MH, Carvalho MM, Mendes FA, Saraiva LM, Juliano MA, 50. Greenfield JP, Tsai J, Gouras GK, Hai B, Thinakaran G, Checler F, Sisodia Juliano L, Garcia-Abreu J, Ferreira ST. Amyloid-beta binds to the extra- SS, Greengard P, Xu H. Endoplasmic reticulum and trans-Golgi network cellular cysteine- rich domain of Frizzled and inhibits Wnt/beta-catenin generate distinct populations of Alzheimer beta-amyloid peptides. Proc signaling. J Biol Chem. 2008;283(14):9359–68. Natl Acad Sci USA. 1999;96(2):742–7. 72. Yan J, Liu XH, Han MZ, Wang YM, Sun XL, Yu N, Li T, Su B, Chen ZY. Block- 51. Sudoh S, Kawamura Y, Sato S, Wang R, Saido TC, Oyama F, Sakaki Y, age of GSK3β-mediated Drp1 phosphorylation provides neuroprotec- Komano H, Yanagisawa K. Presenilin 1 mutations linked to familial tion in neuronal and mouse models of Alzheimer’s disease. Neurobiol Alzheimer’s disease increase the intracellular levels of amyloid beta-pro- Aging. 2015;36(1):211–27. tein 1-42 and its N-terminally truncated variant(s) which are generated 73. Imahori K, Uchida T. Physiology and pathology of tau protein kinases in at distinct sites. J Neurochem. 1998;71(4):1535–43. relation to Alzheimer’s disease. J Biochem. 1997;121(2):179–88. 52. Nah J, Yuan J, Jung YK. Autophagy in neurodegenerative diseases: from 74. Echeverria V, Ducatenzeiler A, Dowd E, Janne J, Grant SM, Szyf M, Wan- mechanism to therapeutic approach. Mol Cells. 2015;38(5):381–9. dosell F, Avila J, Grimm H, Dunnett SB, et al. Altered mitogen-activated 53. UamekKozio M, Furmaga-Jaboska W, Januszewski S, Brzozowska J, protein kinase signaling, tau hyperphosphorylation and mild spatial Scilewska M, Jaboski M, Pluta R. Neuronal autophagy: self-eating or self- learning dysfunction in transgenic rats expressing the beta-amyloid cannibalism in Alzheimer’s disease. Neurochem Res. 2013;38:1769–73. peptide intracellularly in hippocampal and cortical neurons. Neurosci- 54. Son SM, Jung ES, Shin HJ, Byun J, Mook-Jung I. Aβ-induced formation ence. 2004;129(3):583–92. of autophagosomes is mediated by RAGECaMKK β-AMPK signaling. 75. Espana J, Gimenez-Llort L, Valero J, Minano A, Rabano A, Rodriguez- Neurobiol Aging. 2012;33:1006.e11–23. Alvarez J, LaFerla FM, Saura CA. Intraneuronal beta-amyloid accumula- 55. Bayer TA, Wirths O, Majtenyi K, Hartmann T, Multhaup G, Beyreuther K, tion in the amygdala enhances fear and anxiety in Alzheimer’s disease Czech C. Key factors in Alzheimer’s disease: beta-amyloid precursor pro- transgenic mice. Biol Psychiatry. 2010;67(6):513–21. tein processing, metabolism and intraneuronal transport. Brain Pathol. 76. Trojanowski JQ, Mawal-Dewan M, Schmidt ML, Martin J, Lee VM. Locali- 2001;11(1):1–11. zation of the mitogen activated protein kinase ERK2 in Alzheimer’s 56. Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman disease neurofibrillary tangles and senile plaque neurites. Brain Res. CW. Apoptosis is induced by beta-amyloid in cultured central nervous 1993;618(2):333–7. system neurons. Proc Natl Acad Sci USA. 1993;90(17):7951–5. 77. Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke- 57. Versen LL, Mortishire-Smith RJ, Pollack SJ, Shearman MS. The toxicity Iqbal I. Up- regulation of mitogen-activated protein kinases ERK1/2 in vitro of beta-amyloid protein. Biochem J. 1995;311(Pt 1):1–16. and MEK1/2 is associated with the progression of neurofibril- 58. Parihar MS, Hemnani T. Alzheimer’s disease pathogenesis and therapeu- lary degeneration in Alzheimer’s disease. Brain Res Mol Brain Res. tic interventions. J Clin Neurosci. 2004;11(5):456–67. 2002;109(1–2):45–55. 59. Hoshi M, Takashima A, Noguchi K, Murayama M, Sato M, Kondo S, 78. Harada T, Morooka T, Ogawa S, Nishida E. ERK induces p35, a neuron- Saitoh Y, Ishiguro K, Hoshino T, Imahori K. Regulation of mitochondrial specific activator of Cdk5, through induction of Egr1. Nat Cell Biol. pyruvate dehydrogenase activity by tau protein kinase I/glycogen syn- 2001;3(5):453–9. thase kinase 3beta in brain. Proc Natl Acad Sci USA. 1996;93(7):2719–23. 79. Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family 60. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase of protein kinases with diverse biological functions. Microbiol Mol Biol kinase-3. Trends Biochem Sci. 2004;29(2):95–102. Rev. 2004;68(2):320–44. 61. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s 80. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, disease. J Neurochem. 2008;104(6):1433–9. Fumagalli S, Kozma SC, Thomas G. S6K1(−/−)/S6K2(−/−) mice exhibit 62. Gomez-Sintes R, Hernandez F, Lucas JJ, Avila J. GSK-3 mouse models to perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine study neuronal apoptosis and neurodegeneration. Front Mol Neurosci. mRNA translation and reveal a mitogen-activated protein kinase- 2011;4:45. dependent S6 kinase pathway. Mol Cell Biol. 2004;24(8):3112–24. 63. Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. 81. Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gomez C, Ambrosio Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in S. Active, phosphorylation-dependent mitogen-activated protein Majd et al. BMC Neurosci (2015) 16:69 Page 10 of 13 kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal 102. Saunders AM. Apolipoprotein E and Alzheimer disease: an update kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and on genetic and functional analyses. J Neuropathol Exp Neurol. Dementia with Lewy bodies. J Neural Transm. 2001;108(12):1383–96. 2000;59(9):751–8. 82. Ferrer I, Blanco R, Carmona M, Puig B. Phosphorylated mitogen-acti- 103. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone vated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), protein in patients with cerebral and systemic amyloid. Neurosci Lett. stress- activated protein kinase (SAPK/JNK-P), and calcium/calmodulin- 1992;135(2):235–8. dependent kinase II (CaM kinase II) are differentially expressed in tau 104. Fleming LM, Weisgraber KH, Strittmatter WJ, Troncoso JC, Johnson deposits in neurons and glial cells in tauopathies. J Neural Transm. GV. Differential binding of apolipoprotein E isoforms to tau and other 2001;108(12):1397–415. cytoskeletal proteins. Exp Neurol. 1996;138(2):252–60. 83. Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative 105. Ly S, Altman R, Petrlova J, Lin Y, Hilt S, Huser T, Laurence TA, Voss JC. foldopathies. Biochim Biophys Acta. 2005;1739(2–3):298–310. Binding of apolipoprotein E inhibits the oligomer growth of amyloid- 84. Lambourne SL, Sellers LA, Bush TG, Choudhury SK, Emson PC, Suh YH, beta peptide in solution as determined by fluorescence cross-correla- Wilkinson LS. Increased tau phosphorylation on mitogen-activated tion spectroscopy. J Biol Chem. 2013;288(17):11628–35. protein kinase consensus sites and cognitive decline in transgenic 106. Smith JD. Apolipoprotein E4: an allele associated with many diseases. models for Alzheimer’s disease and FTDP-17: evidence for distinct Ann Med. 2000;32(2):118–27. molecular processes underlying tau abnormalities. Mol Cell Biol. 107. Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz 2005;25(1):278–93. GS. Lipoproteins in the central nervous system. Ann N Y Acad Sci. 85. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;903:167–75. 2000;407(6805):802–9. 108. Carter DB, Dunn E, McKinley DD, Stratman NC, Boyle TP, Kuiper SL, 86. Brown A. Axonal transport of membranous and nonmembranous Oostveen JA, Weaver RJ, Boller JA, Gurney ME. Human apolipoprotein cargoes: a unified perspective. J Cell Biol. 2003;160(6):817–21. E4 accelerates beta-amyloid deposition in APPsw transgenic mouse 87. Mandelkow E, Song YH, Schweers O, Marx A, Mandelkow EM. On the brain. Ann Neurol. 2001;50(4):468–75. structure of microtubules, tau, and paired helical filaments. Neurobiol 109. Cho KH, Durbin DM, Jonas A. Role of individual amino acids of apolipo- Aging. 1995;16(3):347–54. protein A-I in the activation of lecithin: cholesterol acyltransferase and 88. Iqbal K, Alonso AC, Gong CX, Khatoon S, Pei JJ, Wang JZ, Grundke-Iqbal in HDL rearrangements. J Lipid Res. 2001;42(3):379–89. I. Mechanisms of neurofibrillary degeneration and the formation of 110. Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer’s neurofibrillary tangles. J Neural Transm Suppl. 1998;53:169–80. amyloid beta-peptide-associated free radical oxidative stress and 89. Brion JP. Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol. neurotoxicity. J Struct Biol. 2000;130(2–3):184–208. 1998;40(3):130–40. 111. Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress 90. Dickson TC, King CE, McCormack GH, Vickers JC. Neurochemical diver- and neurotoxicity: implications for neurodegeneration in Alzheimer’s sity of dystrophic neurites in the early and late stages of Alzheimer’s disease brain. A review. Free Radic Res. 2002;36(12):1307–13. disease. Exp Neurol. 1999;156(1):100–10. 112. Butterfield DA, Griffin S, Munch G, Pasinetti GM. Amyloid beta-peptide 91. Vickers JC, Dickson TC, Adlard PA, Saunders HL, King CE, McCormack and amyloid pathology are central to the oxidative stress and inflam- G. The cause of neuronal degeneration in Alzheimer’s disease. Prog matory cascades under which Alzheimer’s disease brain exists. J Neurobiol. 2000;60(2):139–65. Alzheimers Dis. 2002;4(3):193–201. 92. Masliah E, Terry RD, DeTeresa RM, Hansen LA. Immunohistochemical 113. Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, quantification of the synapse-related protein synaptophysin in Alzhei- Obrenovich ME, Perry G, Smith MA. Role of mitochondrial dysfunction mer disease. Neurosci Lett. 1989;103(2):234–9. in Alzheimer’s disease. J Neurosci Res. 2002;70(3):357–60. 93. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. Comparison 114. Spuch C, Ortolano S, Navarro C. New insights in the amyloid-Beta of neurodegenerative pathology in transgenic mice overexpressing interaction with mitochondria. J Aging Res. 2012;2012:324968. V717F beta-amyloid precursor protein and Alzheimer’s disease. J Neu- 115. Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mito- rosci. 1996;16(18):5795–811. chondrial targeting and a novel transmembrane arrest of Alzheimer’s 94. Henriques AG, Vieira SI, da Cruz ESEF, da Cruz ESOA. Abeta promotes amyloid precursor protein impairs mitochondrial function in neuronal Alzheimer’s disease-like cytoskeleton abnormalities with consequences cells. J Cell Biol. 2003;161(1):41–54. to APP processing in neurons. J Neurochem. 2010;113(3):761–71. 116. Miranda S, Opazo C, Larrondo LF, Munoz FJ, Ruiz F, Leighton F, Inestrosa 95. Braak H, Del Tredici K. Alzheimer’s disease: intraneuronal altera- NC. The role of oxidative stress in the toxicity induced by amyloid beta- tions precede insoluble amyloid-beta formation. Neurobiol Aging. peptide in Alzheimer’s disease. Prog Neurobiol. 2000;62(6):633–48. 2004;25(6):713–8 (discussion 743–716). 117. DiCiero Miranda M, de Bruin VM, Vale MR, Viana GS. Lipid peroxidation 96. Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Serrano J, Bentura and nitrite plus nitrate levels in brain tissue from patients with Alzhei- ML, Martinez-Murillo R, Martinez A, Rodrigo J. Intra- and extracellular mer’s disease. Gerontology. 2000;46(4):179–84. Abeta and PHF in clinically evaluated cases of Alzheimer’s disease. 118. Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Histol Histopathol. 2004;19(3):823–44. Bradshaw PC. Mitochondrial amyloid-beta levels are associated with 97. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, the extent of mitochondrial dysfunction in different brain regions and Sahara N, Skipper L, Yager D, et al. Enhanced neurofibrillary degen- the degree of cognitive impairment in Alzheimer’s transgenic mice. J eration in transgenic mice expressing mutant tau and APP. Science. Alzheimers Dis. 2010;20(Suppl 2):S535–50. 2001;293(5534):1487–91. 119. Lloret A, Fuchsberger T, Giraldo E, Vina J. Molecular mechanisms link- 98. Mudher A, Lovestone S. Alzheimer’s disease-do tauists and baptists ing amyloid β toxicity and Tau hyperphosphorylation in Alzheimer’s finally shake hands? Trends Neurosci. 2002;25(1):22–6. disease. Free Radic Biol Med. 2015;83:186–91. 99. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, 120. Reddy PH. Amyloid precursor protein-mediated free radicals and oxida- Hudspeth B, Chen C, Zhao Y, et al. Beta-amyloid oligomers induce tive damage: implications for the development and progression of phosphorylation of tau and inactivation of insulin receptor substrate via Alzheimer’s disease. J Neurochem. 2006;96(1):1–13. c-Jun N-terminal kinase signalling: suppression by omega-3 fatty acids 121. Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of and curcumin. J Neurosci. 2009;29(28):9078–89. 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxida- 100. Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tan- tion, in the brain in Mild Cognitive Impairment and early Alzheimer’s gles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. disease. Neurobiol Aging. 2006;27(8):1094–9. 2001;293(5534):1491–5. 122. Marmol F, Rodriguez CA, Sanchez J, Chamizo VD. Anti-oxidative 101. Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM. effects produced by environmental enrichment in the hip - Age-dependent induction of congophilic neurofibrillary tau inclusions pocampus and cerebral cortex of male and female rats. Brain Res. in tau transgenic mice. Am J Pathol. 2001;158(2):555–62. 2015;10(1613):120–9. Majd et al. BMC Neurosci (2015) 16:69 Page 11 of 13 123. Butterfield DA, Kanski J. Brain protein oxidation in age-related neuro - 148. Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. Dopamine-dependent degenerative disorders that are associated with aggregated proteins. neurotoxicity of alpha-synuclein: a mechanism for selective neurode- Mech Ageing Dev. 2001;122(9):945–62. generation in Parkinson disease. Nat Med. 2002;8(6):600–6. 124. Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in 149. Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Alzheimer’s disease. J Neurochem. 2000;75(1):436–9. Neurol. 1996;55(3):259–72. 125. Shringarpure R, Grune T, Davies KJ. Protein oxidation and 20S 150. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero proteasome-dependent proteolysis in mammalian cells. Cell Mol Life I, Vidal L, Hoenicka J, Rodriguez O, Atares B, et al. The new mutation, Sci. 2001;58(10):1442–50. E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. 126. Pratico D, Delanty N. Oxidative injury in diseases of the central nervous Ann Neurol. 2004;55(2):164–73. system: focus on Alzheimer’s disease. Am J Med. 2000;109(7):577–85. 151. George JM, Jin H, Woods WS, Clayton DF. Characterization of a novel 127. Broe GA, Grayson DA, Creasey HM, Waite LM, Casey BJ, Bennett HP, protein regulated during the critical period for song learning in the Brooks WS, Halliday GM. Anti-inflammatory drugs protect against zebra finch. Neuron. 1995;15(2):361–72. Alzheimer disease at low doses. Arch Neurol. 2000;57(11):1586–91. 152. Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Gold- 128. Wu Q, Combs C, Cannady SB, Geldmacher DS, Herrup K. Beta-amyloid stein JM, Soriano F, Seubert P, et al. Red blood cells are the major source activated microglia induce cell cycling and cell death in cultured corti- of alpha-synuclein in blood. Neurodegener Dis. 2008;5(2):55–9. cal neurons. Neurobiol Aging. 2000;21(6):797–806. 153. Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K. Demon- 129. Benveniste EN, Nguyen VT, O’Keefe GM. Immunological aspects stration of alpha-synuclein immunoreactivity in neuronal and glial of microglia: relevance to Alzheimer’s disease. Neurochem Int. cytoplasm in normal human brain tissue using proteinase K and formic 2001;39(5–6):381–91. acid pretreatment. Exp Neurol. 2002;176(1):98–104. 130. Szczepanik AM, Funes S, Petko W, Ringheim GE. IL-4, IL-10 and IL-13 154. Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P. Alpha- modulate A beta(1–42)-induced cytokine and chemokine production synuclein and Parkinson’s disease. FASEB J. 2004;18(6):617–26. in primary murine microglia and a human monocyte cell line. J Neuro- 155. Perrin RJ, Woods WS, Clayton DF, George JM. Interaction of human immunol. 2001;113(1):49–62. alpha-Synuclein and Parkinson’s disease variants with phospholip- 131. Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K. Cell mediators ids. Structural analysis using site-directed mutagenesis. J Biol Chem. of inflammation in the Alzheimer disease brain. Alzheimer Dis Assoc 2000;275(44):34393–8. Disord. 2000;14(Suppl 1):S47–53. 156. Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, 132. Raina AK, Zhu X, Rottkamp CA, Monteiro M, Takeda A, Smith MA. Cyclin’ Orrison B, Chen A, Ellis CE, Paylor R, et al. Synaptic vesicle deple- toward dementia: cell cycle abnormalities and abortive oncogenesis in tion correlates with attenuated synaptic responses to prolonged Alzheimer disease. J Neurosci Res. 2000;61(2):128–33. repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 133. Arendt T, Holzer M, Gartner U. Neuronal expression of cycline depend- 2002;22(20):8797–807. ent kinase inhibitors of the INK4 family in Alzheimer’s disease. J Neural 157. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Transm. 1998;105(8–9):949–60. Alpha-synuclein cooperates with CSPalpha in preventing neurodegen- 134. Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict eration. Cell. 2005;123(3):383–96. the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci. 158. Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, 1998;18(8):2801–7. Savalle M, Nemani V, Chaudhry FA, Edwards RH, et al. Alpha-synuclein 135. Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement overexpression in PC12 and chromaffin cells impairs catecholamine of cell cycle elements, cyclin-dependent kinases, pRb, and E2F × DP, release by interfering with a late step in exocytosis. J Neurosci. B-amyloid-induced neuronal death. J Biol Chem. 1999;274(27):19011–6. 2006;26(46):11915–22. 136. Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal 159. Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC. cell death in Alzheimer’s disease. J Neurosci. 2001;21(8):2661–8. Alpha-synuclein promotes SNARE-complex assembly in vivo and 137. Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle in vitro. Science. 2010;329(5999):1663–7. events at all stages of Alzheimer’s disease. J Neurosci. 2003;23(7):2557–63. 160. Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji 138. Raina AK, Monteiro MJ, McShea A, Smith MA. The role of cell H, Shinoda T, Hisanaga S, Ueda K. Tubulin seeds alpha-synuclein fibril cycle-mediated events in Alzheimer’s disease. Int J Exp Pathol. formation. J Biol Chem. 2002;277(3):2112–7. 1999;80(2):71–6. 161. Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada 139. Zhu X, Raina AK, Boux H, Simmons ZL, Takeda A, Smith MA. Activation A, Saito T, Kaji H, Yoshii M, et al. Demonstration of a role for alpha-synu- of oncogenic pathways in degenerating neurons in Alzheimer disease. clein as a functional microtubule-associated protein. J Alzheimers Dis. Int J Dev Neurosci. 2000;18(4–5):433–7. 2004;6(4):435–42 (discussion 443–439). 140. Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM, 162. Zhou RM, Huang YX, Li XL, Chen C, Shi Q, Wang GR, Tian C, Wang ZY, Canonico PL, Nicoletti F, Sortino MA. Mitotic signaling by beta-amyloid Jing YY, Gao C, et al. Molecular interaction of alpha-synuclein with causes neuronal death. FASEB J. 1999;13(15):2225–34. tubulin influences on the polymerization of microtubule in vitro and 141. Copani A, Uberti D, Sortino MA, Bruno V, Nicoletti F, Memo M. Activa- structure of microtubule in cells. Mol Biol Rep. 2010;37(7):3183–92. tion of cell-cycle-associated proteins in neuronal death: a mandatory or 163. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg dispensable path? Trends Neurosci. 2001;24(1):25–31. MS, Shen J, Takio K, Iwatsubo T. alpha-Synuclein is phosphorylated in 142. Majd S, Zarifkar A, Rastegar K, Takhshid MA. Different fibrillar Abeta 1-42 synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4. concentrations induce adult hippocampal neurons to reenter various 164. Uversky VN. Neuropathology, biochemistry, and biophysics of alpha- phases of the cell cycle. Brain Res. 2008;1218:224–9. synuclein aggregation. J Neurochem. 2007;103(1):17–37. 143. Zhang M, Li J, Chakrabarty P, Bu B, Vincent I. Cyclin-dependent kinase 165. Tenreiro S, Reimao-Pinto MM, Antas P, Rino J, Wawrzycka D, Macedo D, inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion Rosado-Ramos R, Amen T, Waiss M, Magalhaes F, et al. Phosphorylation formation, and motor defects in Niemann-Pick Type C mice. Am J modulates clearance of alpha-synuclein inclusions in a yeast model of Pathol. 2004;165(3):843–53. Parkinson’s disease. PLoS Genet. 2014;10:e1004302. 144. Majd S, Chegini F, Chataway T, Zhou XF, Gai W. Reciprocal induction 166. Mahul-Mellier AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, between alpha-synuclein and beta-amyloid in adult rat neurons. Neu- Lamontanara AJ, Bisquertt A, Eliezer D, Masliah E, et al. c-Abl phospho- rotox Res. 2013;23(1):69–78. rylates alpha-synuclein and regulates its degradation, implication for 145. Nagy Z. The last neuronal division: a unifying hypothesis for the patho- alpha-synuclein clearance and contribution to the pathogenesis of genesis of Alzheimer’s disease. J Cell Mol Med. 2005;9(3):531–41. Parkinson’s Disease. Hum Mol Genet. 2014;23(11):2858–79. 146. Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L. Autophagy in aging 167. Tamo W, Imaizumi T, Tanji K, Yoshida H, Mori F, Yoshimoto M, Takahashi and neurodegenerative diseases: implications for pathogenesis and H, Fukuda I, Wakabayashi K, Satoh K. Expression of alpha-synuclein, therapy. Neurobiol Aging. 2014;35:941–57. the precursor of non-amyloid beta component of Alzheimer’s 147. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. disease amyloid, in human cerebral blood vessels. Neurosci Lett. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40. 2002;326(1):5–8. Majd et al. BMC Neurosci (2015) 16:69 Page 12 of 13 168. Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman 189. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, BT, McLean PJ. Formation of toxic oligomeric alpha-synuclein species in Marsden CD. Alterations in glutathione levels in Parkinson’s disease and living cells. PLoS One. 2008;3(4):e1867. other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 169. Paik SR, Shin HJ, Lee JH, Chang CS, Kim J. Copper(II)-induced self- 1994;36(3):348–55. oligomerization of alpha-synuclein. Biochem J. 1999;340(Pt 3):821–8. 190. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD. 170. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E. Increased nigral iron content and alterations in other metal ions occur- Oxidative stress induces amyloid-like aggregate formation of NACP/ ring in brain in Parkinson’s disease. J Neurochem. 1989;52(6):1830–6. alpha-synuclein in vitro. Neuroreport. 1999;10(4):717–21. 191. Spina MB, Cohen G. Dopamine turnover and glutathione oxida- 171. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are devel- tion: implications for Parkinson disease. Proc Natl Acad Sci USA. opmentally expressed, and alpha-synuclein regulates the size of the 1989;86(4):1398–400. presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 192. Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, Wong J, 2000;20(9):3214–20. Takenouchi T, Hashimoto M, Masliah E. alpha-Synuclein promotes mito- 172. Zhu M, Li J, Fink AL. The association of alpha-synuclein with membranes chondrial deficit and oxidative stress. Am J Pathol. 2000;157(2):401–10. affects bilayer structure, stability, and fibril formation. J Biol Chem. 193. Li WW, Yang R, Guo JC, Ren HM, Zha XL, Cheng JS, Cai DF. Localization 2003;278(41):40186–97. of alpha-synuclein to mitochondria within midbrain of mice. Neurore- 173. Jo E, Darabie AA, Han K, Tandon A, Fraser PE, McLaurin J. alpha- port. 2007;18(15):1543–6. Synuclein-synaptosomal membrane interactions: implications for 194. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. Mitochon- fibrillogenesis. Eur J Biochem. 2004;271(15):3180–9. drial association of alpha-synuclein causes oxidative stress. Cell Mol Life 174. Scott D, Roy S. alpha-Synuclein inhibits intersynaptic vesicle Sci. 2008;65(7–8):1272–84. mobility and maintains recycling-pool homeostasis. J Neurosci. 195. Dryanovski D, Guzman J, Xie Z, Galteri D, Volpicelli-Daley L, Lee V, Miller 2012;32(30):10129–35. R, Schumacker P, Surmeier D. Calcium entry and α-synuclein inclusions 175. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, elevate dendritic mitochondrial oxidant stress in dopaminergic neu- Hyman BT, McLean PJ, Unni VK. Distinct roles in vivo for the ubiquitin- rons. J Neurosci. 2013;33(24):10154–64. proteasome system and the autophagy-lysosomal pathway in the 196. Zaltieri M, Longhena F, Pizzi M, Missale C, Spano P, Bellucci A. Mitochon- degradation of α- synuclein. J Neurosci. 2011;31:14508–20. drial Dysfunction and α-synuclein Synaptic Pathology in Parkinson’s 176. Pan PY, Yue Z. Genetic causes of Parkinson’s disease and their links Disease: Who’s on First. Parkinsons Dis. 2015;108029:1–10. to autophagy regulation. Parkinsonism Relat Disord. 2014;20(Suppl 197. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic 1):S154–7. program in cell-free extracts: requirement for dATP and cytochrome c. 177. Iwata A, Miura S, Kanazawa I, Sawada M, Nukina N. alpha-Synuclein Cell. 1996;86(1):147–57. forms a complex with transcription factor Elk-1. J Neurochem. 198. Thayanidhi N, Helm JR, Nycz DC, Bentley M, Liang Y, Hay JC. Alpha- 2001;77(1):239–52. synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in 178. Sidhu A, Wersinger C, Vernier P. Does alpha-synuclein modulate mammalian cells by antagonizing ER/Golgi SNAREs. Mol Biol Cell. dopaminergic synaptic content and tone at the synapse? FASEB J. 2010;21(11):1850–63. 2004;18(6):637–47. 199. Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK. 179. Iwata A, Maruyama M, Kanazawa I, Nukina N. alpha-Synuclein Accumulation of toxic alpha-synuclein oligomer within endoplas- affects the MAPK pathway and accelerates cell death. J Biol Chem. mic reticulum occurs in alpha-synucleinopathy in vivo. J Neurosci. 2001;276(48):45320–9. 2012;32(10):3301–5. 180. Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, 200. Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW, Johnson Nukina N. Alpha-synuclein degradation by serine protease neurosin: E, Smith L, Aoki KR, Dolly JO. Evaluation of the therapeutic usefulness of implication for pathogenesis of synucleinopathies. Hum Mol Genet. botulinum neurotoxin B, C1, E, and F compared with the long lasting 2003;12(20):2625–35. type A. Basis for distinct durations of inhibition of exocytosis in central 181. Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, neurons. J Biol Chem. 2003;278(2):1363–71. Flavell RA. JNK-mediated induction of cyclooxygenase 2 is required for 201. Chen L, Jin J, Davis J, Zhou Y, Wang Y, Liu J, Lockhart PJ, Zhang J. neurodegeneration in a mouse model of Parkinson’s disease. Proc Natl Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochem Acad Sci USA. 2004;101(2):665–70. Biophys Res Commun. 2007;356(3):548–53. 182. Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B. 202. Soper JH, Roy S, Stieber A, Lee E, Wilson RB, Trojanowski JQ, Burd CG, alpha-Synuclein shares physical and functional homology with 14-3-3 Lee VM. Alpha-synuclein-induced aggregation of cytoplasmic vesicles proteins. J Neurosci. 1999;19(14):5782–91. in Saccharomyces cerevisiae. Mol Biol Cell. 2008;19(3):1093–103. 183. Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson’s 203. Gosavi N, Lee HJ, Lee JS, Patel S, Lee SJ. Golgi fragmentation occurs in disease: proximal triggers, distal effectors, and final steps. Apoptosis. the cells with prefibrillar alpha-synuclein aggregates and precedes the 2009;14(4):478–500. formation of fibrillar inclusion. J Biol Chem. 2002;277(50):48984–92. 184. Karunakaran S, Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar 204. Lee HJ, Khoshaghideh F, Lee S, Lee SJ. Impairment of microtubule- S, Ravindranath V. Activation of apoptosis signal regulating kinase 1 dependent trafficking by overexpression of alpha-synuclein. Eur J (ASK1) and translocation of death-associated protein, Daxx, in sub- Neurosci. 2006;24(11):3153–62. stantia nigra pars compacta in a mouse model of Parkinson’s disease: 205. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, protection by alpha-lipoic acid. FASEB J. 2007;21(9):2226–36. Nicoll RA, Edwards RH. Increased expression of alpha-synuclein reduces 185. Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, neurotransmitter release by inhibiting synaptic vesicle reclustering after McGeer PL. Alpha-synuclein activates stress signalling protein kinases in endocytosis. Neuron. 2010;65(1):66–79. THP-1 cells and microglia. Neurobiol Aging. 2008;29(5):739–52. 206. Saha AR, Hill J, Utton MA, Asuni AA, Ackerley S, Grierson AJ, Miller CC, 186. Wilms H, Rosenstiel P, Romero-Ramos M, Arlt A, Schafer H, Seegert D, Davies AM, Buchman VL, Anderton BH, et al. Parkinson’s disease alpha- Kahle PJ, Odoy S, Claasen JH, Holzknecht C, et al. Suppression of MAP synuclein mutations exhibit defective axonal transport in cultured kinases inhibits microglial activation and attenuates neuronal cell death neurons. J Cell Sci. 2004;117(Pt 7):1017–24. induced by alpha-synuclein protofibrils. Int J Immunopathol Pharmacol. 207. Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, 2009;22(4):897–909. Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an 187. Camilleri A, Vassallo N. The centrality of mitochondria in the patho- unrecognized component of amyloid in Alzheimer disease. Proc Natl genesis and treatment of Parkinson’s disease. CNS Neurosci Ther. Acad Sci USA. 1993;90(23):11282–6. 2014;20(7):591–602. 208. Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, et al. 188. Eisbach SE, Outeiro TF. Alpha-synuclein and intracellular trafficking: Extensive nuclear localization of alpha-synuclein in normal rat brain impact on the spreading of Parkinson’s disease pathology. J Mol Med neurons revealed by a novel monoclonal antibody. Neuroscience. (Berl). 2013;91(6):693–703. 2007;145(2):539–55. Majd et al. BMC Neurosci (2015) 16:69 Page 13 of 13 209. Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, Allsop D, 211. Gallardo G, Schluter OM, Sudhof TC. A molecular pathway of neurode- Hassan AH, Jensen PH, El-Agnaf OM. Detection of elevated levels of generation linking alpha-synuclein to ApoE and Abeta peptides. Nat soluble alpha-synuclein oligomers in post-mortem brain extracts Neurosci. 2008;11(3):301–8. from patients with dementia with Lewy bodies. Brain. 2009;132(Pt 4):1093–101. 210. Yang Y, Varvel NH, Lamb BT, Herrup K. Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models. J Neurosci. 2006;26(3):775–84. Submit your next manuscript to BioMed Central and take full advantage of: Convenient online submission Thorough peer review No space constraints or color ﬁgure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

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Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

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Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

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