- Open Access
Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways
BMC Neuroscience volume 16, Article number: 69 (2015)
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 deterioration 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.
Protein misfolding and aggregation contribute to the pathophysiology of neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD). In physiological situations protein misfolding is sensed by the cellular control systems as a threat which is then followed by an immediate response. Any delay detecting the misfolded proteins, may result in damage and progression of neurodegenerative disorders [1, 2]. Unfortunately, not all the cellular responses to misfolded proteins are neuroprotective. Activation of some intracellular pathways as a part of this response occasionally create further damage, interruption in synaptic connections and neuronal apoptosis [3, 4].
Pathophysiology of toxic proteins
All the proteins implicated in neurodegenerative diseases share the common pattern of dysfunctional structure due to an unusual folding [5–7]. Through folding, proteins acquire the three dimensional structures required to undertake their biological functions. This process is prone to errors, causing the protein not to acheive its functional structure, building a toxic protein deposition. When an aggregation status is established, disaggregation rarely occurs because under physiological conditions, the equilibrium is in favour of aggregation [8–11]. These early aggregates are believed to be the source of toxicity in neurodegenerative disorders.
Alzheimer’s disease (AD)
AD is the most common form of dementia and among the leading causes of death in adults. AD is associated with two main lesions: extracellular plaques made of beta-amyloid (Aβ) and intracellular neurofibrillary tangles (NFT) made of tau protein [12, 13]. The plaques are the consequences of abnormal protein folding and aggregation with direct and indirect toxic effects on neuronal survival [14, 15].
Aβ biochemical structure and toxicity
Aβ, the principle protein implicated in development of AD, is derived from amyloid precursor protein (APP). More than ten isoforms of the protein are characterized by different lengths of amino acid chains, and among them APP695 is exclusively expressed in neurons. The transmembrane region of APP is placed near the c-terminus, and contains a Kunitz-type protease inhibitor (KPI) domain, which acts as a potent inhibitor of coagulation factors IXa and XIa, however, APP695 lacks the KPI domain [16, 17].
APP can act as a receptor for a signalling glycoprotein F-spondin that is released by neurons and possesses roles in axonal guidance, neuronal differentiation and neuro-repair [18, 19]. Some other functions of APP have also been proposed, including serving as a link between kinesin and synaptic vesicles being an adhesion protein, a role in metal ion homeostasis, neuroprotection and a function relating to promotion of neurite growth [16, 20].
APP is degraded in lysosomes [21–23] (Fig. 1). Aβ is produced when a normal cleavage of APP occurs α and β secretase cleave APP, outside the membrane. Also three members of a family of peptidase proteins, ADAM, (a disintegrin and metalloproteinase) have a recognized role cleaving the extracellular portion of APP, in the same way that α-secretase does . Proteolysis of APP by β-secretase cleaves APP695 after Met-596 and produces a large soluble N-terminal (sAPPβ) and a small membrane-bound C-terminal fragment (C99), sAPPβ, is neuroprotective and regulates synaptic plasticity. This larger fragment of APP can also act as a microtubule associated protein (MAP) .
APP can undergo proteolysis at the cell surface. Its C99 fragment can be processed by γ- secretase, presenilin 1 and 2, γ-secretase produces Aβ isoforms of 1-40, 1-42 or 1-43 [17, 26–28]. These peptides are made throughout life, but in AD they accumulate due to either increased production or decreased degradation or removal. Remaining Aβ has the potential to enhance its own production in cerebrovascular smooth muscles and hippocampal neurons [29, 30]. Excess peptides, particular those of Aβ 1-40, 1-42 and 1-43, form toxic aggregates, which result in progression of AD [16, 31, 32].
Filaments of amyloid structure are approximately 10 nm wide and 0.1–10 μm long with a β-sheet structure in their motif [33, 34]. Using Electron Paramagnetic Resonance Spectroscopy (EPRS) the β-sheet structure was obtained for both Aβ 1-40 and 1–42, two of the most toxic forms of amyloid protein [35, 36].
Aβ oligomers can be generated both extra- and intracellularly. Extracellular Aβ toxicity could be mediated through binding to receptors such as NMDA and disrupting the calcium balance of the neuron [37, 38]. Extracellular Aβ is internalized, stored in the lysosomes and can leak into the cytosol by destabilization of the lysosome membrane. Aβ oligomers have the ability to inhibit the function of proteasomes causing neuronal apoptosis [39, 40]. Toxicity of fibrillar and oligomers of Aβ also occurs through cytoskeletal disruption, tangle development, loss of synapses and inhibition of hippocampal long-term potentiation (LTP). This is the so-called “Aβ cascade theory” of AD [12, 41, 42].
Intracellular inclusions of Aβ have been found within neuronal compartments. [43, 44]. Internalization of Aβ occurs either via binding to low-density lipoprotein related protein-2 (LRP2) , LRP-1 [46, 47] or to a receptor for advanced glycation end-product (RAGE) . The presence of Aβ in various subcellular compartments, suggests different sites for APP proteolysis, such as Aβ40 in the trans-Golgi network and Aβ42 in the endoplasmic reticulum (ER) [49, 50] as well as Golgi compartments . Autophagic vacuoles enriched with presenilin-1 (PS1), APP and Aβ are found frequently in degenerating neurons in patients with AD. This suggests an essential role for autophagy in clearing the aggregated peptide through a lysosomal-dependent pathway .
Aβ disrupts APP trafficking, and initiates a pathological cascade of Aβ accumulation [39, 43]. An accumulation of vacuoles filled with Aβ occurs as a result of interruption to neuronal trafficking associated with the disruption of autopghgosomes . Aβ itself is also able to activate the adenosine monophosphate kinase (AMPK) pathway, generating more autophagic vacuoles . Thus, AD patients appear to produce abundant extracellular Aβ, resulting in plaque formation with a high level of toxicity causing extensive neuronal apoptosis [55–57].
Aß and kinases
Glycogen synthase kinase-3 beta (GSK-3β)
Glycogen synthase kinase-3 beta (GSK-3β) is well-known for its role in glycogen metabolism, activation of transcription factors and phosphorylation of tau. GSK3 is modulated through a variety of pathways including wnt, phosphatidylinositide-3 kinase (PI3K) and Akt deactivate GSK-3β by phosphorylating Ser9 [58, 59], increasing GSK-3β, in pre-tangles which is closely associated with tangle-bearing neurons suggesting a role in tau hyperphosphorylation in AD [60–64]. A recent report associated GSK-3β gene variants with the level of tau and Aβ42 in cerebrospinal fluid in AD as well as cognitive function . Further in vivo evidence of GSK-3β’s role in AD has come from transgenic mouse models over-expressing this kinase with a presentation of tau hyper-phosphorylation, astrocytosis, and neuronal death [66, 67]. The concurrent hyper-phosphorylation of other cellular structures such as presinilines, β-catenin and GSK3-cAMP responsive element-binding protein also produces some of the pathological features of AD [61, 68, 69].
Aβ exposure induces GSK-3β activity, extensive phosphorylation of tau and cell death. Aβ inhibits PI3K and Akt pathways and inactivates the wnt cascade,. Because these pathways eventually deactivate GSK3, their inhibition will result in hyperactivity of GSK3 [70, 71] (Fig. 2). This Aβ-induced GSK-3β hyperactivity triggers the mitochondrial fragmentation leading to neuronal apoptosis . GSK-3β also interacts with pyruvate dehydrogenase (PDH), thereby reducing levels of acetyl-CoA .
Mitogen-activated protein kinases (MAPK)
Aβ affects another intracellular second messenger the extracellular signal regulated Kinase (ERK)/MAPK pathway [74, 75]. MAPKs are a family of serine/threonine kinases that contribute to the hyperprocessing of APP and hyper-phosphorylation of tau associated with AD [76, 77]. MAPKs phosphorylate proteins with regulatory functions including other kinases, transcription factors and enzymes [78–80]. Stimulation of MAPK by Aβ in a Ras-dependent manner, leads to tau phosphorylation [81–84]. It has also been demonstrated that activation of MAPK by neurotrophins as well as Aβ induces p35, the specific activator of cyclin dependent kinase 5 (cdk5) in the cell cycle. Thus another means of damaging the neuron through MAPK activation by Aβ could be re-activation of the cell cycle, which is considered a lethal event for neurons [78–85].
Aß, cytoskeleton and axonal transport
A constant interaction between microtubules and MAPs such as tau is a necessary element for axonal transport . Tau holds the microtubular tracks in place and plays a key role in their stability . When tau is subjected to hyper-phosphorylation, it loses the ability to bind to microtubules and to maintain their structure, causing tau aggregation into paired helical filaments (PHF) and NFTs . The number of NFTs is linked to the degree of dementia, suggesting a correlation between NFT, dystrophic neurite formation and neuronal dysfunction [89–91]. It seems that interrupting axonal transport will interrupt neuronal function and lead to eventual death [92–94].
Deposition of Aβ plaques precedes tau phosphorylation and exerts a damaging effect upon the cytoskeleton giving rise to PHF formation. . Intraneuronal formation of Aβ also happens prior to appearance of PHF, making it the upstream step in triggering the neurodegenerative events [95, 96].
Further evidence that Aβ formation precedes PHF formation comes from a tau mutation study when tau mutation produced tau-inclusion tangles but not plaques, however, APP or presenilin mutations caused both plaques and tangles. Transgenic mice doubly mutant for mutant APP and tau have more tangles than mice with the single mutant tau transgene [97, 98]. Tau phosphorylation occurs through activation of c-Jun N-terminal kinase (JNK), a member of MAPK . In a study, amyloid injections exacerbated tangle pathology in mutant-tau mice but why Aβ injections did not stimulate tau pathology with wild-type tau is not known , when other transgenic mice overexpressing wild-type tau exhibited tangles .
Aβ and apolipoprotein E (apoE)
ApoE is a normal constituent of cells. In the nervous system, it acts as the main lipid transport protein with a wide variety of roles in intracellular signalling, immune modulation, glucose metabolism, lipid movement and lipoprotein metabolism . ApoE has been detected in the amyloid plaques in AD .
The ability of ApoE to interact with Aβ, demonstrated its critical role in amyloid deposition and clearance [91, 102, 104]. The apoE4 allele of ApoE is associated with high cholesterol in cardiovascular disease and particularly AD, however, the apoE2 allele confers some protection against hypercholesterolemia [102, 105, 106]. ApoE2 and E3 formed stable complexes with Aβ at levels of 20 fold greater than those occurring with apoE4 . The greater affinity of ApoE2 and E3 for Aβ protects neurons from neurotoxic effects of Aβ by facilitating the uptake of these complexes by apoE receptors. Conversely, apoE4 accelerates Aβ deposition and progression/growth of Aβ seeds to larger Aβ plaques [108, 109].
Aβ, mitochondria and oxidative stress
Post-mortem studies revealed a wide range of Aβ-derived mitochondrial dysfunction in AD patients [113–115]. Intracellular Aβ can be localized to mitochondrial membranes, where it interrupts the normal mitochondrial function through blocking mitochondrial channels and inhibiting mitochondrial protein activity. By blocking the electron transport chain, Aβ accumulation leads to an increase in reactive oxygen species (ROS), causing oxidative stress [114, 116–118] (Fig. 3) which leads to a deregulation of the ROS signalling pathway in AD . Superoxide radicals, produced due to mitochondrial dysfunction oxidate different neuronal compartments such as proteins, lipids and DNA [117, 120]. The evidence of oxidative damage in patients with mild cognitive dementia (MCD) shows that the oxidation insult occurs as one of the first steps of AD . Chronic oxidative stress inhibits tau dephosphorylation by inhibiting tau phosphatase as well as increasing the phosphorylation of tau by activating p38 .
The other aspect of oxidative stress relates to protein oxidation. Oxidative modification of proteins is important in aging and age-related neurodegenerative disorders . Protein oxidation results in protein dysfunction associated with conformational changes. The oxidized protein may also have a higher resistance to proteolysis and protein cross-linking and aggregation will be increased . The aggregated misfolded proteins then get trapped in proteasome’s pore leading to proteasomal dysfunction [124, 125]. A vicious cycle of misfolded protein accumulation is then established.
Aggregated peptides have the potential to initiate oxidative stress through cellular dysfunction leading to calcium accumulation and increased tau polymerization . Oxidative stress also elicits an inflammatory response  through microglial activation [128, 129] and release of pro inflammatory cytokines , promoting inflammation and invasion of Aβ plaques by astrocytes  which mature plaques into neuritic plaques, a common finding in AD patients.
Aβ and cell cycle
Inappropriate cell cycle activation is an early event seen in AD brains . Although adult neurons are considered to be in a terminally-differentiated state, accumulation of associated cell cycle-related proteins have been described in degenerating neurons [133–137]. It is assumed that ectopic localization of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors are the results of abortive attempt by neurons to re-enter the cell cycle. Re-entering the cell cycle is a consequence of mitogen factors and perhaps is promoted by the recruitment of mitogenic signal transduction mechanisms [138, 139]. Subjecting neurons to Aβ, forces the cell to re-enter the cell cycle, cross the G1/S phase transition and begin de novo DNA synthesis before apoptotic death occurs [140–142], this could be inhibited by cell-cycle inhibitors [143, 144]. These findings led to the hypothesis that vulnerable neurons re-enter the cell cycle and proceed through S phase, but then abort somatic division and eventually degenerate .
Parkinson’s disease (PD)
Parkinson’s disease (PD) is the second most common neurodegenerative disorder among the adults. The progressive impaired motor function in patients with PD is an outcome of dopaminergic neuronal loss particularly in the substantia nigra (SN) . 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 possession of a hydrophobic region of amino acids from 66 to 95 . As a vesicle associated protein, the main functions of α-Syn are regulating membrane stability, neuronal plasticity, synaptic rearrangement, controlling vesicular trafficking and neurotransmission through a chaperon-like function to other proteins [134, 155–159]. Due to the ability α-Syn to interact with tubulin, α-Syn also shows a microtubule-associated activity [160–162].
Lesions from autopsied PD brains show a marked increase in S129 hyperphosphorylated α-Syn  which creates high molecular weight α-Syn with a high potential for self-assembly. This makes it a likely candidate to be a toxic protein in the event of aggregation [164, 165]. α-Syn could also be phosphorylated on Tyr39 with no link between this phosphorylation and pathological features .
Fibrillar α-Syn as the main component of LBs, is present in many dying cells in PD , however, oligomeric α-Syn also possesses enough toxicity to damage neurons . The process of misfolding of α-Syn has been shown to be accelerated by many metals such as copper  and ferric ion and also by elevated intracellular cytochrome c . Conformational changes leads to protein misfolding reduce the ability of α-Syn to interact with the vesicular trafficking and modulating neurotransmission [171–174]. Conformational changes and consequent aggregation α-Syn also triggers a cascade of neuronal response such as autophagy, one of the main pathways of α-Syn degradation [175, 176].
α-Synuclein and MAPK
Regulation of MAPK pathway is a downstream effect of α-Syn. In neurons, α-Syn binding to MAPK inhibits this pathway. In particular, α-Syn binds directly to ERK2 and indirectly to Elk-1, which is also an ERK2 substrate . Thus α-Syn reduces dopamine transporter (DAT) insertion in the synaptic membranes of axonal terminals . α-Syn also decreases MAPK activation through reducing the phosphorylation of p38 and down regulating c-fos gene [179, 180].
Phosphorylation and accumulation of MAPK elements have been reported in PD patients [81, 172]. One of the MAPK elements is JNK, that is phosphorylated in PD and activates the transcription factor of c-jun. Activation of c-jun increases the level of cell death genes expression in dopaminergic neurons [82, 181]. JNK also inhibits Bcl-2 survival protein by activation of pro-apoptotic proteins of Bad and Bim [182, 183]. The misregulation of MAPK eventually leads to neuronal apoptosis. Inhibiting JNK phosphorylation, however, can protect neurons from death . Activation of ERK has also been reported in glial cells which consequently starts a cascade of inflammatory responses and blocking that pathway reduces microglial activation [185, 186].
α-Synuclein and oxidative stress
α-Syn overexpression causes the impairment of mitochondrial homeostasis  leading to oxidative stress and dopamine oxidation . Formation of giant mitochondria and laminated bodies, autophagozomes, decreased MTT levels, reduction of glutathione and high levels of iron, in brain tissue confirmed the presence of oxidative stress as a common finding in PD [189–193] Oxidative stress affects the Ca2+ shift and balance in cytoplasm, leading to stimulation of mitochondrial nitric oxide synthase (mtNOS) [194, 195]. α-Syn also has the ability of binding to pro apoptotic protein BAD, a member of Bcl-2 family . As the result of this attachment, Bcl-2 protein is removed from mitochondrial pores, allowing cytochrome c to be released from the mitochondria. This event triggers neuronal apoptosis demonstrating a link between mitochondrial dysfunction and synaptic accumulation of α-Syn in PD [195, 196].
α-Synuclein and axonal trafficking
α-Syn ability to act as a MAP, allows microtubules to maintain their stability, to carry cargos in an energy-dependent manner, and to facilitate neurotransmitter release [159, 161]. Overexpression and phosporylation of α-Syn, however, affects the normal function of ER and Golgi system. α-Syn directly binds to ER and the Golgi apparatus and inhibits the soluble NSF attachment protein receptor (SNARE) complex assembly [197, 198]. The SNARE complex is made of vesicular SNARE proteins (v-SNARE) and target membrane SNARE proteins (t-SNARE). It possesses the ability of self-assembly and allows vesicular fusion to cell membrane [199, 200]. Blocking this assembly by α-Syn overexpression interferes with neurotransmitter release and reuptake (Fig. 4). Consequently, relocating cellular proteins within the cell or from the cell toward the membrane and eventual neurotransmission will be disturbed . The eventual outcome would include protein accumulation inside the cell, Golgi system fragmentation, a decrease in neurotransmitter release and neuronal apoptosis [202–204]. α-Syn also reduces polymerization of tubulin. Whether reducing polymerization of tubulin is a direct outcome or an indirect one, through generating mitochondrial dysfunction and lack of ATP for polymerization, the outcome represents itself as a disrupted axonal transport and neurite degeneration [20, 203, 205].
α-Syn and Aβ interaction
Both AD and PD show similar clinical presentations in their mid to late stages [206, 207] suggesting the possibility of interaction between α-Syn and Aβ [25, 144, 208]. It has been shown that instead of immediate cell death, affected neurons live for several months in a near- functional state [209, 210]. Constant production of both proteins allows continuing protein–protein interaction and as a result, a reciprocal induction between α-Syn and Aβ could cause a gradual increase in the protein levels of both types, before neurodegeneration commences . The PI3K pathway and ApoE could contribute to this interaction, as manipulation of PI3K reduced the reciprocal elevation of α-Syn and Aβ . Deletion of ApoE in α-Syn transgenic mice decreased the levels of Aβ, thereby alleviating the onset of disease . More research is still required to achieve a complete understanding of the underlying mechanisms.
Although the process of neuronal death is a common feature in AD and PD, the underlying mechanisms are still under investigation. Some aspects of toxicity may be specific for a distinct type of neurodegenerative disorder however common cellular mechanisms with a substantial overlap underlie the neuronal responses to the toxic proteins.
In conclusion, neuronal death in neurodegenerative disorders is not a single-cause event and establishing the exact links between the activation mechanisms in response to toxic proteins could open a window for promising therapeutic interventions.
amyloid precursor protein
cyclin dependent kinase
extracellular signal regulated kinase
glycogen synthase kinase-3 Beta
Jun N-terminal kinase
Kunitz-type protease inhibitor
low-density lipoprotein related protein-2
mitogen-activated protein kinases
mitochondrial nitric oxide synthase
nerve growth factor
paired helical filaments
reactive oxygen species
NSF attachment protein receptor
target membrane SNARE protein
vesicular SNARE protein
Uversky VN. Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol Life Sci. 2003;60(9):1852–71.
Stefani M, Rigacci S. Protein folding and aggregation into amyloid: the interference by natural phenolic compounds. Int J Mol Sci. 2013;14(6):12411–57.
Kakizuka A. Protein precipitation: a common etiology in neuro-degenerative disorders? Trends Genet. 1998;14(10):396–402.
Kopito RR, Ron D. Conformational disease. Nat Cell Biol. 2000;2(11):E207–9.
Karpinar DP, Balija MB, Kugler S, Opazo F, Rezaei-Ghaleh N, Wender N, Kim HY, Taschenberger G, Falkenburger BH, Heise H, et al. Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models. EMBO J. 2009;28(20):3256–68.
Borgia MB, Borgia A, Best RB, Steward A, Nettels D, Wunderlich B, Schuler B, Clarke J. Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. Nature. 2011;474(7353):662–5.
Norrby E. Prions and protein-folding diseases. J Intern Med. 2011;270(1):1–14.
Stefani M. Protein misfolding and aggregation: new examples in medicine and biology of the dark side of the protein world. Biochim Biophys Acta. 2004;1739(1):5–25.
Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J. 2008;27(2):336–49.
Abelein A, Bolognesi B, Dobson CM, Graslund A, Lendel C. Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid beta self-assembly. Biochemistry. 2012;51(1):126–37.
Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(6):777–94.
Selkoe DJ. 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. 2000;924:17–25.
Kumar S, Wirths O, Theil S, Gerth J, Bayer TA, Walter J. Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer’s disease. Acta Neuropathol. 2013;125(5):699–709.
Lansbury PT Jr. Structural neurology: are seeds at the root of neuronal degeneration? Neuron. 1997;19(6):1151–4.
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, et al. 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. 2006;26(40):10129–40.
Storey E, Cappai R. The amyloid precursor protein of Alzheimer’s disease and the Abeta peptide. Neuropathol Appl Neurobiol. 1999;25(2):81–97.
Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta- and gamma- secretases. FEBS Lett. 2000;483(1):6–10.
Ho A, Sudhof TC. 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. 2004;101(8):2548–53.
Schubert D, Klar A, Park M, Dargusch R, Fischer WH. F-spondin promotes nerve precursor differentiation. J Neurochem. 2006;96(2):444–53.
Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron. 2000;28(2):449–59.
Gouras GK, Xu H, Jovanovic JN, Buxbaum JD, Wang R, Greengard P, Relkin NR, Gandy S. Generation and regulation of beta-amyloid peptide variants by neurons. J Neurochem. 1998;71(5):1920–5.
Schneider A, Rajendran L, Honsho M, Gralle M, Donnert G, Wouters F, Hell SW, Simons M. Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci. 2008;28(11):2874–82.
Sarajarvi T, Tuusa JT, Haapasalo A, Lackman JJ, Sormunen R, Helisalmi S, Roehr JT, Parrado AR, Makinen P, Bertram L, et al. Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking. Mol Cell Biol. 2011;31(11):2326–40.
Wang X, Huang T, Bu G, Xu H. Dysregulation of protein trafficking in neurodegeneration. Mol Neurodegenr. 2014;9(31):1–9.
Olah J, Vincze O, Virok D, Simon D, Bozso Z, Tokesi N, Horvath I, Hlavanda E, Kovacs J, Magyar A, et al. Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. J Biol Chem. 2011;286(39):34088–100.
Howlett DR, Simmons DL, Dingwall C, Christie G. In search of an enzyme: the beta-secretase of Alzheimer’s disease is an aspartic proteinase. Trends Neurosci. 2000;23(11):565–70.
Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009;29(41):13042–52.
Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M. Familial Alzheimer’s disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J Neurochem. 2005;94(5):1189–201.
Davis-Salinas J, Saporito-Irwin SM, Cotman CW, Van Nostrand WE. Amyloid beta-protein induces its own production in cultured degenerating cerebrovascular smooth muscle cells. J Neurochem. 1995;65(2):931–4.
Majd S, Rastegar K, Zarifkar A, Takhshid MA. Fibrillar beta-amyloid (Abeta) (1-42) elevates extracellular Abeta in cultured hippocampal neurons of adult rats. Brain Res. 2007;1185:321–7.
Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, et al. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol. 2004;165(4):1289–300.
Yamamoto K, Shimada H, Koh H, Ataka S, Miki T. Serum levels of albumin-amyloid beta complexes are decreased in Alzheimer’s disease. Geriatr Gerontol Int. 2014;14(3):716–23.
Sunde M, Blake CC. From the globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q Rev Biophys. 1998;31:1–39.
Benzinger TL, Gregory DM, Burkoth TS, Miller-Auer H, Lynn DG, Botto RE, Meredith SC. Propagating structure of Alzheimer’s beta-amyloid(10-35) is parallel beta-sheet with residues in exact register. Proc Natl Acad Sci USA. 1998;95:13407–12.
Tycko R. Insights into the amyloid folding problem from solid-state NMR. Biochemistry. 2003;42:3151–9.
Torok M, Milton S, Kayed R, Wu P, McIntire T, Glabe CG, Langen R. Structural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J Biol Chem. 2002;277:40810–5.
Yanagisawa K. Role of gangliosides in Alzheimer’s disease. Biochim Biophys Acta. 2002;1768:1943–51.
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL. 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. 2002;282:11590–601.
Laferla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci. 2007;8:499–509.
Almeida CG, Takahashi RH, Gouras GK. Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci. 2006;26:4277–88.
Huse JT, Doms RW. Closing in on the amyloid cascade: recent insights into the cell biology of Alzheimer’s disease. Mol Neurobiol. 2000;22(1–3):81–98.
Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer’s disease. Brain. 2006;129(Pt 11):2840–55.
Wertkin AM, Turner RS, Pleasure SJ, Golde TE, Younkin SG, Trojanowski JQ, Lee VM. 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. 1993;90(20):9513–7.
Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002;161(5):1869–79.
Alvira-Botero X, Perez-Gonzalez R, Spuch C, Vargas T, Antequera D, Garzon M, Bermejo-Pareja F, Carro E. Megalin interacts with APP and the intracellular adapter protein FE65 in neurons. Mol Cell Neurosci. 2010;45(3):306–15.
Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron. 2007;56(1):66–78.
Spuch C, Ortolano S, Navarro C. LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer’s disease. Front Physiol. 2012;3:269.
Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, et al. RAGE-mediated signalling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci USA. 2009;106(47):20021–6.
Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM, Doms RW. Alzheimer’s Abeta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med. 1997;3(9):1021–3.
Greenfield JP, Tsai J, Gouras GK, Hai B, Thinakaran G, Checler F, Sisodia SS, Greengard P, Xu H. Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci USA. 1999;96(2):742–7.
Sudoh S, Kawamura Y, Sato S, Wang R, Saido TC, Oyama F, Sakaki Y, Komano H, Yanagisawa K. 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. 1998;71(4):1535–43.
Nah J, Yuan J, Jung YK. Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Mol Cells. 2015;38(5):381–9.
UamekKozio M, Furmaga-Jaboska W, Januszewski S, Brzozowska J, Scilewska M, Jaboski M, Pluta R. Neuronal autophagy: self-eating or self-cannibalism in Alzheimer’s disease. Neurochem Res. 2013;38:1769–73.
Son SM, Jung ES, Shin HJ, Byun J, Mook-Jung I. Aβ-induced formation of autophagosomes is mediated by RAGECaMKK β-AMPK signaling. Neurobiol Aging. 2012;33:1006.e11–23.
Bayer TA, Wirths O, Majtenyi K, Hartmann T, Multhaup G, Beyreuther K, Czech C. Key factors in Alzheimer’s disease: beta-amyloid precursor protein processing, metabolism and intraneuronal transport. Brain Pathol. 2001;11(1):1–11.
Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW. Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA. 1993;90(17):7951–5.
Versen LL, Mortishire-Smith RJ, Pollack SJ, Shearman MS. The toxicity in vitro of beta-amyloid protein. Biochem J. 1995;311(Pt 1):1–16.
Parihar MS, Hemnani T. Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci. 2004;11(5):456–67.
Hoshi M, Takashima A, Noguchi K, Murayama M, Sato M, Kondo S, Saitoh Y, Ishiguro K, Hoshino T, Imahori K. Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci USA. 1996;93(7):2719–23.
Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004;29(2):95–102.
Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem. 2008;104(6):1433–9.
Gomez-Sintes R, Hernandez F, Lucas JJ, Avila J. GSK-3 mouse models to study neuronal apoptosis and neurodegeneration. Front Mol Neurosci. 2011;4:45.
Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol. 1999;58(9):1010–9.
Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K. 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. 1996;92(3):232–41.
Kettunen P, Larsson S, Holmgren S, Olsson S, Minthon L, Zetterberg H, Blennow K, Nilsson S, Sjölander A. Genetic variants of GSK3B are associated with biomarkers for Alzheimer’s disease and cognitive function. J Alzheimers Dis. 2015;44(4):1313–22.
Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, et al. 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. 2000;275(52):41340–9.
Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 2001;20(1–2):27–39.
Hansen T, Rehfeld JF, Nielsen FC. GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding. NeuroReport. 2004;15(5):841–5.
Jope RS, Yuskaitis CJ, Beurel E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res. 2007;32(4–5):577–95.
Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem. 2007;282(46):33305–12.
Magdesian MH, Carvalho MM, Mendes FA, Saraiva LM, Juliano MA, Juliano L, Garcia-Abreu J, Ferreira ST. Amyloid-beta binds to the extracellular cysteine- rich domain of Frizzled and inhibits Wnt/beta-catenin signaling. J Biol Chem. 2008;283(14):9359–68.
Yan J, Liu XH, Han MZ, Wang YM, Sun XL, Yu N, Li T, Su B, Chen ZY. Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer’s disease. Neurobiol Aging. 2015;36(1):211–27.
Imahori K, Uchida T. Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J Biochem. 1997;121(2):179–88.
Echeverria V, Ducatenzeiler A, Dowd E, Janne J, Grant SM, Szyf M, Wandosell F, Avila J, Grimm H, Dunnett SB, et al. 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. 2004;129(3):583–92.
Espana J, Gimenez-Llort L, Valero J, Minano A, Rabano A, Rodriguez-Alvarez J, LaFerla FM, Saura CA. Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice. Biol Psychiatry. 2010;67(6):513–21.
Trojanowski JQ, Mawal-Dewan M, Schmidt ML, Martin J, Lee VM. Localization of the mitogen activated protein kinase ERK2 in Alzheimer’s disease neurofibrillary tangles and senile plaque neurites. Brain Res. 1993;618(2):333–7.
Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke-Iqbal I. 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. 2002;109(1–2):45–55.
Harada T, Morooka T, Ogawa S, Nishida E. ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nat Cell Biol. 2001;3(5):453–9.
Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004;68(2):320–44.
Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G. 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. 2004;24(8):3112–24.
Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gomez C, Ambrosio S. 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. 2001;108(12):1383–96.
Ferrer I, Blanco R, Carmona M, Puig B. 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. 2001;108(12):1397–415.
Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta. 2005;1739(2–3):298–310.
Lambourne SL, Sellers LA, Bush TG, Choudhury SK, Emson PC, Suh YH, Wilkinson LS. 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. 2005;25(1):278–93.
Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;407(6805):802–9.
Brown A. Axonal transport of membranous and nonmembranous cargoes: a unified perspective. J Cell Biol. 2003;160(6):817–21.
Mandelkow E, Song YH, Schweers O, Marx A, Mandelkow EM. On the structure of microtubules, tau, and paired helical filaments. Neurobiol Aging. 1995;16(3):347–54.
Iqbal K, Alonso AC, Gong CX, Khatoon S, Pei JJ, Wang JZ, Grundke-Iqbal I. Mechanisms of neurofibrillary degeneration and the formation of neurofibrillary tangles. J Neural Transm Suppl. 1998;53:169–80.
Brion JP. Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol. 1998;40(3):130–40.
Dickson TC, King CE, McCormack GH, Vickers JC. Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Exp Neurol. 1999;156(1):100–10.
Vickers JC, Dickson TC, Adlard PA, Saunders HL, King CE, McCormack G. The cause of neuronal degeneration in Alzheimer’s disease. Prog Neurobiol. 2000;60(2):139–65.
Masliah E, Terry RD, DeTeresa RM, Hansen LA. Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett. 1989;103(2):234–9.
Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer’s disease. J Neurosci. 1996;16(18):5795–811.
Henriques AG, Vieira SI, da Cruz ESEF, da Cruz ESOA. Abeta promotes Alzheimer’s disease-like cytoskeleton abnormalities with consequences to APP processing in neurons. J Neurochem. 2010;113(3):761–71.
Braak H, Del Tredici K. Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-beta formation. Neurobiol Aging. 2004;25(6):713–8 (discussion 743–716).
Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Serrano J, Bentura ML, Martinez-Murillo R, Martinez A, Rodrigo J. Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer’s disease. Histol Histopathol. 2004;19(3):823–44.
Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001;293(5534):1487–91.
Mudher A, Lovestone S. Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci. 2002;25(1):22–6.
Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, et al. 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. 2009;29(28):9078–89.
Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001;293(5534):1491–5.
Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM. Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol. 2001;158(2):555–62.
Saunders AM. Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses. J Neuropathol Exp Neurol. 2000;59(9):751–8.
Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992;135(2):235–8.
Fleming LM, Weisgraber KH, Strittmatter WJ, Troncoso JC, Johnson GV. Differential binding of apolipoprotein E isoforms to tau and other cytoskeletal proteins. Exp Neurol. 1996;138(2):252–60.
Ly S, Altman R, Petrlova J, Lin Y, Hilt S, Huser T, Laurence TA, Voss JC. Binding of apolipoprotein E inhibits the oligomer growth of amyloid-beta peptide in solution as determined by fluorescence cross-correlation spectroscopy. J Biol Chem. 2013;288(17):11628–35.
Smith JD. Apolipoprotein E4: an allele associated with many diseases. Ann Med. 2000;32(2):118–27.
Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz GS. Lipoproteins in the central nervous system. Ann N Y Acad Sci. 2000;903:167–75.
Carter DB, Dunn E, McKinley DD, Stratman NC, Boyle TP, Kuiper SL, Oostveen JA, Weaver RJ, Boller JA, Gurney ME. Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. Ann Neurol. 2001;50(4):468–75.
Cho KH, Durbin DM, Jonas A. Role of individual amino acids of apolipoprotein A-I in the activation of lecithin: cholesterol acyltransferase and in HDL rearrangements. J Lipid Res. 2001;42(3):379–89.
Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol. 2000;130(2–3):184–208.
Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res. 2002;36(12):1307–13.
Butterfield DA, Griffin S, Munch G, Pasinetti GM. 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. 2002;4(3):193–201.
Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA. Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res. 2002;70(3):357–60.
Spuch C, Ortolano S, Navarro C. New insights in the amyloid-Beta interaction with mitochondria. J Aging Res. 2012;2012:324968.
Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 2003;161(1):41–54.
Miranda S, Opazo C, Larrondo LF, Munoz FJ, Ruiz F, Leighton F, Inestrosa NC. The role of oxidative stress in the toxicity induced by amyloid beta-peptide in Alzheimer’s disease. Prog Neurobiol. 2000;62(6):633–48.
DiCiero Miranda M, de Bruin VM, Vale MR, Viana GS. Lipid peroxidation and nitrite plus nitrate levels in brain tissue from patients with Alzheimer’s disease. Gerontology. 2000;46(4):179–84.
Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Bradshaw PC. 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. 2010;20(Suppl 2):S535–50.
Lloret A, Fuchsberger T, Giraldo E, Vina J. Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer’s disease. Free Radic Biol Med. 2015;83:186–91.
Reddy PH. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer’s disease. J Neurochem. 2006;96(1):1–13.
Williams TI, Lynn BC, Markesbery WR, Lovell MA. 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. 2006;27(8):1094–9.
Marmol F, Rodriguez CA, Sanchez J, Chamizo VD. Anti-oxidative effects produced by environmental enrichment in the hippocampus and cerebral cortex of male and female rats. Brain Res. 2015;10(1613):120–9.
Butterfield DA, Kanski J. Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech Ageing Dev. 2001;122(9):945–62.
Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in Alzheimer’s disease. J Neurochem. 2000;75(1):436–9.
Shringarpure R, Grune T, Davies KJ. Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells. Cell Mol Life Sci. 2001;58(10):1442–50.
Pratico D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer’s disease. Am J Med. 2000;109(7):577–85.
Broe GA, Grayson DA, Creasey HM, Waite LM, Casey BJ, Bennett HP, Brooks WS, Halliday GM. Anti-inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol. 2000;57(11):1586–91.
Wu Q, Combs C, Cannady SB, Geldmacher DS, Herrup K. Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol Aging. 2000;21(6):797–806.
Benveniste EN, Nguyen VT, O’Keefe GM. Immunological aspects of microglia: relevance to Alzheimer’s disease. Neurochem Int. 2001;39(5–6):381–91.
Szczepanik AM, Funes S, Petko W, Ringheim GE. 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. 2001;113(1):49–62.
Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K. Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis Assoc Disord. 2000;14(Suppl 1):S47–53.
Raina AK, Zhu X, Rottkamp CA, Monteiro M, Takeda A, Smith MA. Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neurosci Res. 2000;61(2):128–33.
Arendt T, Holzer M, Gartner U. Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer’s disease. J Neural Transm. 1998;105(8–9):949–60.
Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci. 1998;18(8):2801–7.
Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F × DP, B-amyloid-induced neuronal death. J Biol Chem. 1999;274(27):19011–6.
Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci. 2001;21(8):2661–8.
Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci. 2003;23(7):2557–63.
Raina AK, Monteiro MJ, McShea A, Smith MA. The role of cell cycle-mediated events in Alzheimer’s disease. Int J Exp Pathol. 1999;80(2):71–6.
Zhu X, Raina AK, Boux H, Simmons ZL, Takeda A, Smith MA. Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int J Dev Neurosci. 2000;18(4–5):433–7.
Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM, Canonico PL, Nicoletti F, Sortino MA. Mitotic signaling by beta-amyloid causes neuronal death. FASEB J. 1999;13(15):2225–34.
Copani A, Uberti D, Sortino MA, Bruno V, Nicoletti F, Memo M. Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path? Trends Neurosci. 2001;24(1):25–31.
Majd S, Zarifkar A, Rastegar K, Takhshid MA. Different fibrillar Abeta 1-42 concentrations induce adult hippocampal neurons to reenter various phases of the cell cycle. Brain Res. 2008;1218:224–9.
Zhang M, Li J, Chakrabarty P, Bu B, Vincent I. Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice. Am J Pathol. 2004;165(3):843–53.
Majd S, Chegini F, Chataway T, Zhou XF, Gai W. Reciprocal induction between alpha-synuclein and beta-amyloid in adult rat neurons. Neurotox Res. 2013;23(1):69–78.
Nagy Z. The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer’s disease. J Cell Mol Med. 2005;9(3):531–41.
Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L. Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy. Neurobiol Aging. 2014;35:941–57.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40.
Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med. 2002;8(6):600–6.
Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol. 1996;55(3):259–72.
Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55(2):164–73.
George JM, Jin H, Woods WS, Clayton DF. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron. 1995;15(2):361–72.
Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Goldstein JM, Soriano F, Seubert P, et al. Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis. 2008;5(2):55–9.
Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K. Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol. 2002;176(1):98–104.
Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P. Alpha-synuclein and Parkinson’s disease. FASEB J. 2004;18(6):617–26.
Perrin RJ, Woods WS, Clayton DF, George JM. Interaction of human alpha-Synuclein and Parkinson’s disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J Biol Chem. 2000;275(44):34393–8.
Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 2002;22(20):8797–807.
Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell. 2005;123(3):383–96.
Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, Savalle M, Nemani V, Chaudhry FA, Edwards RH, et al. Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci. 2006;26(46):11915–22.
Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663–7.
Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Ueda K. Tubulin seeds alpha-synuclein fibril formation. J Biol Chem. 2002;277(3):2112–7.
Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T, Kaji H, Yoshii M, et al. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J Alzheimers Dis. 2004;6(4):435–42 (discussion 443–439).
Zhou RM, Huang YX, Li XL, Chen C, Shi Q, Wang GR, Tian C, Wang ZY, Jing YY, Gao C, et al. Molecular interaction of alpha-synuclein with tubulin influences on the polymerization of microtubule in vitro and structure of microtubule in cells. Mol Biol Rep. 2010;37(7):3183–92.
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4.
Uversky VN. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem. 2007;103(1):17–37.
Tenreiro S, Reimao-Pinto MM, Antas P, Rino J, Wawrzycka D, Macedo D, Rosado-Ramos R, Amen T, Waiss M, Magalhaes F, et al. Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson’s disease. PLoS Genet. 2014;10:e1004302.
Mahul-Mellier AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, Lamontanara AJ, Bisquertt A, Eliezer D, Masliah E, et al. 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. 2014;23(11):2858–79.
Tamo W, Imaizumi T, Tanji K, Yoshida H, Mori F, Yoshimoto M, Takahashi H, Fukuda I, Wakabayashi K, Satoh K. Expression of alpha-synuclein, the precursor of non-amyloid beta component of Alzheimer’s disease amyloid, in human cerebral blood vessels. Neurosci Lett. 2002;326(1):5–8.
Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One. 2008;3(4):e1867.
Paik SR, Shin HJ, Lee JH, Chang CS, Kim J. Copper(II)-induced self-oligomerization of alpha-synuclein. Biochem J. 1999;340(Pt 3):821–8.
Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E. Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport. 1999;10(4):717–21.
Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000;20(9):3214–20.
Zhu M, Li J, Fink AL. The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation. J Biol Chem. 2003;278(41):40186–97.
Jo E, Darabie AA, Han K, Tandon A, Fraser PE, McLaurin J. alpha-Synuclein-synaptosomal membrane interactions: implications for fibrillogenesis. Eur J Biochem. 2004;271(15):3180–9.
Scott D, Roy S. alpha-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. J Neurosci. 2012;32(30):10129–35.
Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ, Unni VK. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α- synuclein. J Neurosci. 2011;31:14508–20.
Pan PY, Yue Z. Genetic causes of Parkinson’s disease and their links to autophagy regulation. Parkinsonism Relat Disord. 2014;20(Suppl 1):S154–7.
Iwata A, Miura S, Kanazawa I, Sawada M, Nukina N. alpha-Synuclein forms a complex with transcription factor Elk-1. J Neurochem. 2001;77(1):239–52.
Sidhu A, Wersinger C, Vernier P. Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J. 2004;18(6):637–47.
Iwata A, Maruyama M, Kanazawa I, Nukina N. alpha-Synuclein affects the MAPK pathway and accelerates cell death. J Biol Chem. 2001;276(48):45320–9.
Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, Nukina N. Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet. 2003;12(20):2625–35.
Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, Flavell RA. JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA. 2004;101(2):665–70.
Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B. alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci. 1999;19(14):5782–91.
Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps. Apoptosis. 2009;14(4):478–500.
Karunakaran S, Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar S, Ravindranath V. 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. 2007;21(9):2226–36.
Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, McGeer PL. Alpha-synuclein activates stress signalling protein kinases in THP-1 cells and microglia. Neurobiol Aging. 2008;29(5):739–52.
Wilms H, Rosenstiel P, Romero-Ramos M, Arlt A, Schafer H, Seegert D, Kahle PJ, Odoy S, Claasen JH, Holzknecht C, et al. Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils. Int J Immunopathol Pharmacol. 2009;22(4):897–909.
Camilleri A, Vassallo N. The centrality of mitochondria in the pathogenesis and treatment of Parkinson’s disease. CNS Neurosci Ther. 2014;20(7):591–602.
Eisbach SE, Outeiro TF. Alpha-synuclein and intracellular trafficking: impact on the spreading of Parkinson’s disease pathology. J Mol Med (Berl). 2013;91(6):693–703.
Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 1994;36(3):348–55.
Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem. 1989;52(6):1830–6.
Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA. 1989;86(4):1398–400.
Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, Wong J, Takenouchi T, Hashimoto M, Masliah E. alpha-Synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000;157(2):401–10.
Li WW, Yang R, Guo JC, Ren HM, Zha XL, Cheng JS, Cai DF. Localization of alpha-synuclein to mitochondria within midbrain of mice. Neuroreport. 2007;18(15):1543–6.
Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci. 2008;65(7–8):1272–84.
Dryanovski D, Guzman J, Xie Z, Galteri D, Volpicelli-Daley L, Lee V, Miller R, Schumacker P, Surmeier D. Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J Neurosci. 2013;33(24):10154–64.
Zaltieri M, Longhena F, Pizzi M, Missale C, Spano P, Bellucci A. Mitochondrial Dysfunction and α-synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First. Parkinsons Dis. 2015;108029:1–10.
Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86(1):147–57.
Thayanidhi N, Helm JR, Nycz DC, Bentley M, Liang Y, Hay JC. Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs. Mol Biol Cell. 2010;21(11):1850–63.
Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK. Accumulation of toxic alpha-synuclein oligomer within endoplasmic reticulum occurs in alpha-synucleinopathy in vivo. J Neurosci. 2012;32(10):3301–5.
Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW, Johnson E, Smith L, Aoki KR, Dolly JO. 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. 2003;278(2):1363–71.
Chen L, Jin J, Davis J, Zhou Y, Wang Y, Liu J, Lockhart PJ, Zhang J. Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochem Biophys Res Commun. 2007;356(3):548–53.
Soper JH, Roy S, Stieber A, Lee E, Wilson RB, Trojanowski JQ, Burd CG, Lee VM. Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae. Mol Biol Cell. 2008;19(3):1093–103.
Gosavi N, Lee HJ, Lee JS, Patel S, Lee SJ. Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J Biol Chem. 2002;277(50):48984–92.
Lee HJ, Khoshaghideh F, Lee S, Lee SJ. Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein. Eur J Neurosci. 2006;24(11):3153–62.
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65(1):66–79.
Saha AR, Hill J, Utton MA, Asuni AA, Ackerley S, Grierson AJ, Miller CC, Davies AM, Buchman VL, Anderton BH, et al. Parkinson’s disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons. J Cell Sci. 2004;117(Pt 7):1017–24.
Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA. 1993;90(23):11282–6.
Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, et al. Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience. 2007;145(2):539–55.
Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, Allsop D, Hassan AH, Jensen PH, El-Agnaf OM. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain. 2009;132(Pt 4):1093–101.
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.
Gallardo G, Schluter OM, Sudhof TC. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat Neurosci. 2008;11(3):301–8.
SM, HG and JP conceived and drafted the manuscript. All authors read and approved the final manuscript.
SM was a member of Alzheimer’s and Parkinson’s lab at Flinders University of South Australia when she started writing the manuscript and we would like to thank the lab members for their enthusiastic discussions about protein toxicity in neurodegenerative disorders.
The authors declare that they have no competing interests.
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Majd, S., Power, J.H. & Grantham, H.J.M. Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways. BMC Neurosci 16, 69 (2015) doi:10.1186/s12868-015-0211-1
- Alzheimer’s disease
- Parkinson’s disease
- Intracellular signalling