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Cited by 374Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchParkinson's Disease Mechanisms and Treatments

α-synuclein in the pathophysiology of Alzheimer’s disease

Open access
Twohig, Daniel, Nielsen, Henrietta M.·2019·Molecular Neurodegeneration
DOI 10.1186/s13024-019-0320-xPMC PMC6558879
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Abstract

The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD. Lewy-related pathology (LRP), primarily comprised of αSyn, is present in a majority of autopsied AD brains, and higher levels of αSyn in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD have been linked to cognitive decline. Recent studies also suggest that the asymptomatic accumulation of Aβ plaques is associated with higher CSF αSyn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of Aβ and the APOEε4 allele, the latter being a major genetic risk factor for both AD and DLB. In this review, we provide a summary of the current evidence proposing an involvement of αSyn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of αSyn structure and inferred function.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes clinical, post-mortem, CSF, and experimental evidence that α-synuclein (αSyn) contributes to Alzheimer’s disease (AD) pathophysiology alongside amyloid-β and tau. It proposes αSyn may act as an active or passive player, with APOEε4 and GSK3β-mediated tau phosphorylation as possible links.

Key findings

  • Co-morbid Lewy-related pathology (LRP) is reported in more than 50% of autopsy-confirmed AD brains, and more than 90% of patients with PSEN1 autosomal dominant AD exhibit αSyn pathology specifically in the amygdala; LRP frequently co-localizes with tau and less often with Aβ.
  • CSF αSyn is reduced in synucleinopathies such as PD and DLB, but unaltered or slightly increased in MCI and AD; higher CSF αSyn is associated with progression from MCI to AD, lower MMSE scores, and in ADAD mutation carriers correlates with estimated years from symptom onset. In MCI patients who converted to AD, APOEε4 showed a dose-response relationship with CSF αSyn, with homozygous carriers exhibiting the highest concentrations.
  • Experimental evidence links αSyn to tau hyperphosphorylation via GSK3β, to Aβ oligomerization and toxicity, and to APOE: αSyn can seed tau and Aβ aggregation, APOE4 reduces αSyn uptake in oligodendrocytes, and A30P/ApoE-KO mice had increased survival and reduced Aβ aggregates.
  • αSyn is a 140-residue (14-kDa) protein with an N-terminal region, a hydrophobic NAC region (a.a. 61–95), and an acidic C-terminal region; PD-causing mutations A30P, E46K, A53T, G51D, and H50Q reside within conserved repeat motifs.

Methods

  • Narrative review; no systematic search strategy or meta-analysis is described.
  • Synthesizes post-mortem human AD brain studies (Table 1), CSF biomarker studies in AD, MCI, DLB, PD, and controls (Table 2), and in vitro and transgenic mouse experiments.
  • Main analysis is a qualitative synthesis of reported associations and proposed pathophysiological mechanisms.

Limitations

  • Stated: consensus on a CSF αSyn profile in synucleinopathies is still lacking mainly due to high variability between αSyn quantification assays, differences in the species of αSyn being quantified, and inter-laboratory variability.
  • Stated: experimental results are not fully consistent, and inter-model variability and heterogeneity have so far precluded identification of exact mechanisms.
  • Evident: as a narrative review, it provides no new primary data or systematic bias assessment; many cited links are correlational, and causality remains to be established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s13024-019-0320-x

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 170 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    A recent study described a novel link between the APOEε4 risk allele, cerebrospinal fluid αSyn levels and amyloid-β deposition at the very early stages of Alzheimer's disease development.

    “our recent study described a novel link between the APOEε4 risk allele, CSF αSyn levels and Aβ deposition at the very early stages of AD development [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Twohig D, Rodriguez-Vieitez E, Sando SB, Berge G, Lauridsen C, Moller I, Grontvedt GR, Brathen G, Patra K, Bu G, et al. The relevance of cerebrospinal fluid alpha-synuclein levels to sporadic and familial Alzheimer's disease. Acta Neuropathol Commun. 2018;6:130. source

      Not checked in the free run.

  • Premisecitation

    Post-mortem Alzheimer's disease brains without detectable Lewy-related pathology have significantly increased levels of intracellular soluble αSyn monomers and oligomers in the inferior temporal lobe.

    “two reports from Larson, Lesné and co-workers demonstrated significantly increased levels of intracellular soluble αSyn monomers and oligomers in the inferior temporal lobe of AD brains without any detectable LRP [69, 73].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Larson ME, Sherman MA, Greimel S, Kuskowski M, Schneider JA, Bennett DA, Lesne SE. Soluble alpha-synuclein is a novel modulator of Alzheimer's disease pathophysiology. J Neurosci. 2012;32:10253–66. source

      Not checked in the free run.

    • cites [73] Larson ME, Greimel SJ, Amar F, LaCroix M, Boyle G, Sherman MA, Schley H, Miel C, Schneider JA, Kayed R, et al. Selective lowering of synapsins induced by oligomeric alpha-synuclein exacerbates memory deficits. Proc Natl Acad Sci U S A. 2017;114:E4648–57. source

      Not checked in the free run.

  • Premisecitation

    αSyn monomers, dimers, trimers and pentamers bind to monomeric amyloid-β in post-mortem samples from Alzheimer's disease and dementia with Lewy bodies brains.

    “Co-immunoprecipitation experiments have shown that αSyn monomers, dimers, trimers and pentamers bind to monomeric Aβ in post-mortem samples from AD and DLB brains [67].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, Spencer B, Rockenstein E, Trejo M, Platoshyn O, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One. 2008;3:e3135. source

      Not checked in the free run.

  • Interpretationreasoning

    Accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, is involved in the pathophysiology of Alzheimer's disease.

    “accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The co-occurrence of αSyn pathology with Alzheimer’s disease pathology and the association of cerebrospinal fluid αSyn levels with Alzheimer’s disease-related measures indicate that αSyn contributes to Alzheimer’s disease pathophysiology rather than being an incidental bystander.
  • Premisecitation

    Co-morbid αSyn pathology has been reported in more than half of all autopsy-confirmed Alzheimer's disease cases.

    “co-morbid αSyn pathology has been reported in more than half of all autopsy-confirmed AD cases [22–24]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St George-Hyslop P, et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998;153:1365–70. source

      Not checked in the free run.

    • cites [23] Hamilton RL. Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000;10:378–84. source

      Not checked in the free run.

    • cites [24] Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y. α-Synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Res. 2001;888:287–96. source

      Not checked in the free run.

  • May combine two claims. 34
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    Post-mortem Alzheimer's disease brains exhibited increased 17-, 28-, 35- and 56-kDa, but not 72-kDa αSyn species, which correlated to Alzheimer's disease-related cognitive decline and reduced synapsin expression within the temporal lobe.

    “post-mortem AD brains exhibited increased 17-, 28-, 35- and 56-kDa, but not 72-kDa αSyn species, which correlated to AD-related cognitive decline and reduced synapsin expression within the temporal lobe.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Larson ME, Sherman MA, Greimel S, Kuskowski M, Schneider JA, Bennett DA, Lesne SE. Soluble alpha-synuclein is a novel modulator of Alzheimer's disease pathophysiology. J Neurosci. 2012;32:10253–66. source

      Not checked in the free run.

    • cites [73] Larson ME, Greimel SJ, Amar F, LaCroix M, Boyle G, Sherman MA, Schley H, Miel C, Schneider JA, Kayed R, et al. Selective lowering of synapsins induced by oligomeric alpha-synuclein exacerbates memory deficits. Proc Natl Acad Sci U S A. 2017;114:E4648–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Co-occurrence of Lewy-related pathology in Alzheimer's disease is frequently associated with the immunohistochemical co-localization of αSyn and tau pathology, and to a lesser extent αSyn and amyloid-β pathology.

    “the co-occurrence of LRP in AD is frequently associated with the immunohistochemical co-localization of αSyn and tau pathology [22, 24, 61, 63], and to a lesser extent αSyn and Aβ pathology [62, 65].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [22] Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St George-Hyslop P, et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998;153:1365–70. source

      Not checked in the free run.

    • cites [24] Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y. α-Synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Res. 2001;888:287–96. source

      Not checked in the free run.

    • cites [61] Marui W, Iseki E, Ueda K, Kosaka K. Occurrence of human alpha-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer's disease. J Neurol Sci. 2000;174:81–4. source

      Not checked in the free run.

    • cites [63] Iseki E. Dementia with Lewy bodies: reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease. Neuropathology. 2004;24:72–8. source

      Not checked in the free run.

    • cites [62] Wirths O, Weickert S, Majtenyi K, Havas L, Kahle PJ, Okochi M, Haass C, Multhaup G, Beyreuther K, Bayer TA. Lewy body variant of Alzheimer's disease: alpha-synuclein in dystrophic neurites of A beta plaques. Neuroreport. 2000;11:3737–41. source

      Not checked in the free run.

    • cites [65] Mikolaenko I, Pletnikova O, Kawas CH, O'Brien R, Resnick SM, Crain B, Troncoso JC. Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA). J Neuropathol Exp Neurol. 2005;64:156–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Experimental evidence has linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of amyloid-β and the APOEε4 allele.

    “Experimental evidence has further linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of Aβ and the APOEε4 allele, the latter being a major genetic risk factor for both AD and DLB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Increased presence of potentially toxic forms of soluble intracellular αSyn, direct interactions between oligomeric αSyn and monomeric amyloid-β, and frequent co-localization of αSyn with neurofibrillary tangles and amyloid-β plaques in brain regions susceptible to Alzheimer's disease neurodegeneration may explain the more severe clinical symptoms often found in Alzheimer's disease patients withco

    “Thus, an increased presence of potentially toxic forms of soluble intracellular αSyn, direct interactions between oligomeric αSyn and monomeric Aβ, and the frequent co-localization of αSyn with NFTs and Aβ plaques in brain regions susceptible to AD neurodegeneration may explain the more severe clinical symptoms often found in AD patients with co-occurring LRP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The APOEε4 variant significantly increases the risk of dementia with Lewy bodies, whereas the APOEε2 variant appears to be protective against both Alzheimer's disease and dementia with Lewy bodies.

    “the APOEε4 variant significantly increases the risk of DLB, whereas the APOEε2 variant appears to be protective against both disorders [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Berge G, Sando SB, Rongve A, Aarsland D, White LR. Apolipoprotein E epsilon2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry. 2014;85:1227–31. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Co-occurring Lewy-related pathology may relate to visual hallucinations, extrapyramidal symptoms and a shorter more aggressive disease course.

    “Co-occurring LRP may relate to visual hallucinations [63], extrapyramidal symptoms [51, 53, 72] and a shorter more aggressive disease course [59].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [63] Iseki E. Dementia with Lewy bodies: reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease. Neuropathology. 2004;24:72–8. source

      Not checked in the free run.

    • cites [51] Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, Thal L, Pay MM, Hofstetter R, Klauber M, et al. The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990;40:1–8. source

      Not checked in the free run.

    • cites [53] Forstl H, Burns A, Luthert P, Cairns N, Levy R. The Lewy-body variant of Alzheimer's disease. Clinical and pathological findings. Br J Psychiatry. 1993;162:385–92. source

      Not checked in the free run.

    • cites [72] Portet F, Scarmeas N, Cosentino S, Helzner EP, Stern Y. Extrapyramidal signs before and after diagnosis of incident Alzheimer disease in a prospective population study. Arch Neurol. 2009;66:1120–6. source

      Not checked in the free run.

    • cites [59] Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R, Thal LJ. Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology. 1998;51:351–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a small autosomal dominant Alzheimer's disease kindred study, three related family members carrying the S170F PSEN1 mutation had widespread limbic, neocortical and brainstem Lewy-related pathology, dementia onset during the third decade of life, severe symptoms and death by the fourth to fifth decade of life.

    “three related family members carrying the S170F PSEN1 mutation had widespread limbic, neocortical and brainstem LRP, dementia onset during the third decade of life, severe symptoms and death by the fourth to fifth decade of life [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, Jervis R, Lendon CL, Goate AM, McKeel DW Jr, Morris JC. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol. 2005;62:1821–30. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both αSyn and tau appear to be secreted by similar exosome-mediated release mechanisms and both proteins can be endocytosed via the heparin sulfate proteoglycans pathway.

    “both αSyn and tau appear to be secreted by similar exosome-mediated release mechanisms [99, 100] and both proteins can also be endocytosed via the heparin sulfate proteoglycans (HSPGs) pathway [101].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, Hall GF. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9. source

      Not checked in the free run.

    • cites [100] Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 2010;30:6838–51. source

      Not checked in the free run.

    • cites [101] Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013;110:E3138–47. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NAC is essential in the aggregation of αSyn due to its ability to adopt β-sheet structures and to elicit seeding-competent amyloids.

    “The NAC appears to be essential in the aggregation of αSyn due to its ability to adopt β-sheet structures (Fig. 1c) [115] and has also been shown elicit seeding-competent amyloids [116, 117].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [115] Li HT, Du HN, Tang L, Hu J, Hu HY. Structural transformation and aggregation of human alpha-synuclein in trifluoroethanol: non-amyloid component sequence is essential and beta-sheet formation is prerequisite to aggregation. Biopolymers. 2002;64:221–6. source

      Not checked in the free run.

    • cites [116] Giasson BI, Murray IV, Trojanowski JQ, Lee VM. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J Biol Chem. 2001;276:2380–6. source

      Not checked in the free run.

    • cites [117] Luk KC, Song C, O'Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ, Lee VM. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CSF αSyn levels positively correlate with t-tau in non-mutation and ADAD mutation carriers, and with p-tau in non-mutation carriers and PSEN1 mutation carriers only, not APP or PSEN2 mutation carriers.

    “CSF αSyn levels were positively correlated with t-tau in non-mutation and ADAD mutation carriers, and with p-tau in non-mutation carriers and PSEN1 mutation carriers only (not APP or PSEN2 mutation carriers)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Twohig et al. 2018 [27]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    αSyn is a small 140-residue (14-kDa, pKa=4.7) protein translated from 5 exons of the SNCA gene located on chromosome 4 at 4q21.3-q22.

    “α-synuclein is a small 140-residue (14-kDa, pKa= 4.7) protein translated from 5 exons of the SNCA gene located on the long arm of chromosome four at position 21 (4q21.3-q22) [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Siddiqui IJ, Pervaiz N, Abbasi AA, Bisaglia M, Mammi S, Bubacco L, Vilar M, Kruger R, Zarranz JJ, Silke AC, et al. The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication. Sci Rep. 2016;6:–24475. source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    The direction of the relationship between cerebrospinal fluid αSyn levels and brain amyloid-β plaque burden was positive in asymptomatic Dominantly Inherited Alzheimer Network participants, but changed to negative when symptoms began (CDR>0.5).

    “the direction of this relationship between CSF αSyn levels and brain Aβ plaque burden was positive in DIAN participants that were asymptomatic, however, the direction changed to negative when symptoms began to surface (CDR>0.5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Twohig D, Rodriguez-Vieitez E, Sando SB, Berge G, Lauridsen C, Moller I, Grontvedt GR, Brathen G, Patra K, Bu G, et al. The relevance of cerebrospinal fluid alpha-synuclein levels to sporadic and familial Alzheimer's disease. Acta Neuropathol Commun. 2018;6:130. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Together these results suggest an association between biological processes reflected in altered cerebrospinal fluid αSyn levels and the asymptomatic development of Alzheimer's disease pathology, which in turn may be under the influence of APOEε4.

    “Together these results suggest an association between biological processes reflected in altered CSF αSyn levels and the asymptomatic development of AD pathology, which in turn may be under the influence of APOEε4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The N-terminal and NAC of αSyn can form a single α-helix when bound to low-curvature membranes or two amphipathic anti-parallel α-helices when bound to high-curvature lipid membranes.

    “Multiple in vitro experiments have shown that the N-terminal and NAC of αSyn can form a single α-helix (a.a. 3-92) when bound to membranes of low curvature [106–109] or two amphipathic anti-parallel α-helices (a.a. 3-37 and a.a. 45-92) when bound to lipid membranes of high curvature [103, 110, 111]”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [106] Ferreon AC, Gambin Y, Lemke EA, Deniz AA. Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence. Proc Natl Acad Sci U S A. 2009;106:5645–50. source

      Not checked in the free run.

    • cites [107] Trexler AJ, Rhoades E. Alpha-synuclein binds large unilamellar vesicles as an extended helix. Biochemistry. 2009;48:2304–6. source

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    • cites [108] Trexler AJ, Rhoades E. Function and dysfunction of alpha-synuclein: probing conformational changes and aggregation by single molecule fluorescence. Mol Neurobiol. 2013;47:622–31. source

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    • cites [109] Georgieva ER, Ramlall TF, Borbat PP, Freed JH, Eliezer D. The lipid-binding domain of wild type and mutant alpha-synuclein: compactness and interconversion between the broken and extended helix forms. J Biol Chem. 2010;285:28261–74. source

      Not checked in the free run.

    • cites [103] Ulmer TS, Bax A, Cole NB, Nussbaum RL. Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem. 2005;280:9595–603. source

      Not checked in the free run.

    • cites [110] Davidson WS, Jonas A, Clayton DF, George JM. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem. 1998;273:9443–9. source

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    • cites [111] Zhu M, Li J, Fink AL. The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation. J Biol Chem. 2003;278:40186–97. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The extracellular levels of αSyn and tau may be regulated by similar mechanisms, reflected in a strong consistent correlation between the cerebrospinal fluid concentrations of these proteins in both control subjects and Alzheimer's disease patients.

    “Hence, the extracellular levels of αSyn and tau may be regulated by similar mechanisms reflected in a strong consistent correlation between the CSF concentrations of these proteins in both control subjects and AD patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    αSyn can interact and catalyze the oligomerization of tau, and can form neurotoxic cation pores with Aβ.

    “in vitro and in vivo models have shown that αSyn can interact and catalyze the oligomerization of tau [197], and form neurotoxic cation pores with Aβ [67].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [197] Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003;300:636–40. source

      Not checked in the free run.

    • cites [67] Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, Spencer B, Rockenstein E, Trejo M, Platoshyn O, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One. 2008;3:e3135. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortical shRNA-induced reduction of SNCA expression in rats with complete T10-T11 spinal cord transections increases neuronal survival, decreases apoptosis, and stimulates motor and sensory recovery; upregulation of SNCA exacerbates neuronal death and impedes recovery.

    “cortical shRNA-induced reduction of SNCA expression in rats with complete T10-T11 spinal cord transections, resulted in a significant increase in neuronal survival, decreased apoptosis, and stimulated motor and sensory recovery in the hindquarters. In contrast upregulation of SNCA expression exacerbated neuronal death and impeded recovery [172].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Wang YC, Feng GY, Xia QJ, Hu Y, Xu Y, Xiong LL, Chen ZW, Wang HP, Wang TH, Zhou X. Knockdown of alpha-synuclein in cerebral cortex improves neural behavior associated with apoptotic inhibition and neurotrophin expression in spinal cord transected rats. Apoptosis. 2016;21:404–20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α/β/γ-Syn triple-KO animals are viable but have lower survival rates and age-dependent neuronal dysfunction in the hippocampus and retina.

    “The α/β/γ-Syn triple-KO animals were viable but had lower survival rates and age-dependent neuronal dysfunction in the hippocampus and retina [160].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Greten-Harrison B, Polydoro M, Morimoto-Tomita M, Diao L, Williams AM, Nie EH, Makani S, Tian N, Castillo PE, Buchman VL, Chandra SS. alphabetagamma-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc Natl Acad Sci U S A. 2010;107:19573–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenously added αSyn increases phosphorylation of tau at Ser-396, which can be prevented by the GSK3β inhibitor SB216763.

    “exogenously added αSyn increased the phosphorylation of tau at the Ser-396 site which could be prevented by the GSK3β inhibitor SB216763[188]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Gassowska M, Czapski GA, Pajak B, Cieslik M, Lenkiewicz AM, Adamczyk A. Extracellular alpha-synuclein leads to microtubule destabilization via GSK-3beta-dependent Tau phosphorylation in PC12 cells. PLoS One. 2014;9:e94259. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    αSyn multimers assemble when bound to vesicles engaged in SNARE-dependent exocytosis.

    “Burré and colleagues reported that αSyn multimers assemble when bound to vesicles engaged in SNARE dependent exocytosis [135]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Burre J, Sharma M, Sudhof TC. alpha-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci U S A. 2014;111:E4274–83. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αSyn enhances the toxic oligomerization of Aβ1-42, leading to oligomeric Aβ1-42-mediated cleavage of αSyn and liberation of the NAC.

    “αSyn enhanced the toxic oligomerization of Aβ1-42 leading to oligomeric Aβ1-42 mediated cleavage of αSyn and liberation of the NAC”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R. Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochem Res. 2006;31:1153–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpressing human αSyn in WT mouse neurons retards closure of the fusion pore, reduces the number of exocytotic events, but increases the kinetics of exocytosis.

    “overexpressing human αSyn in WT mice neurons retarded the closure of the fusion pore, reduced the number of exocytotic events, but also increased the kinetics of exocytosis”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Logan T, Bendor J, Toupin C, Thorn K, Edwards RH. α-Synuclein promotes dilation of the exocytotic fusion pore. Nat Neurosci. 2017;20:681–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αSyn KO, β-Syn KO, α/β-Syn double-KO, and γ-Syn KO animals are viable, fertile, display normal brain development, morphology, synaptic ultrastructure, no behavioral abnormalities, and lack a distinguishable phenotype.

    “αSyn knock-out (KO)[155, 156], β-Syn KO [157], α/β-Syn double-KO [157], and γ-Syn KO [158] animals were all viable, fertile, displayed normal brain development, morphology, synaptic ultrastructure, they had no behavioral abnormalities, and lacked any distinguishable phenotype [155–158].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [155] Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25:239–52. source

      Not checked in the free run.

    • cites [156] 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;22:8797–807. source

      Not checked in the free run.

    • cites [157] Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, Sudhof TC. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A. 2004;101:14966–71. source

      Not checked in the free run.

    • cites [158] Ninkina N, Papachroni K, Robertson DC, Schmidt O, Delaney L, O'Neill F, Court F, Rosenthal A, Fleetwood-Walker SM, Davies AM, Buchman VL. Neurons expressing the highest levels of gamma-synuclein are unaffected by targeted inactivation of the gene. Mol Cell Biol. 2003;23:8233–45. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic neuronal cultures overexpressing human αSyn tagged with GFP have augmented synaptic architecture, reduced pre-synaptic protein levels and altered release kinetics.

    “transgenic neuronal cultures had augmented synaptic architecture, reduced pre-synaptic protein levels and altered release kinetics [163]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. A Pathologic Cascade Leading to Synaptic Dysfunction in -Synuclein-Induced Neurodegeneration. J Neurosci. 2010;30:8083–95. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αSyn is degraded by autophagy and the ubiquitin-proteasome system, and by extracellular proteases such as neurosin/kallikrein 6.

    “Several mechanisms have been reported to orchestrate the degradation of αSyn including autophagy and catabolism mediated by the ubiquitin-proteasome system [150]. Also, extracellular proteases like neurosin, also referred to as kallikrein 6, have been shown to degrade αSyn [151, 152].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [150] Kim C, Lee SJ. Controlling the mass action of alpha-synuclein in Parkinson's disease. J Neurochem. 2008;107:303–16. source

      Not checked in the free run.

    • cites [151] Kasai T, Tokuda T, Yamaguchi N, Watanabe Y, Kametani F, Nakagawa M, Mizuno T. Cleavage of normal and pathological forms of alpha-synuclein by neurosin in vitro. Neurosci Lett. 2008;436:52–6. source

      Not checked in the free run.

    • cites [152] Tatebe H, Watanabe Y, Kasai T, Mizuno T, Nakagawa M, Tanaka M, Tokuda T. Extracellular neurosin degrades alpha-synuclein in cultured cells. Neurosci Res. 2010;67:341–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic expression of αSyn completely rescues neurodegeneration in CSPα-/- animals, while loss of endogenous αSyn exacerbates neurodegeneration.

    “transgenic expression of αSyn completely rescued the neurodegeneration in CSPα-/- animals, while loss of endogenous αSyn exacerbated the neurodegeneration [161]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell. 2005;123:383–96. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αSyn exclusively co-localizes with synaptophysin, and knockdown of αSyn significantly reduces the distal/reserve pool of synaptic vesicles.

    “αSyn was shown to exclusively co-localize with the transmembrane synaptic vesicle protein synaptophysin [162]. Ultrastructural analysis further revealed that knock-down of αSyn resulted in a significant reduction in the distal/reserve pool of synaptic vesicles [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] 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;20:3214–20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The C-terminal of αSyn can directly interact with the microtubule binding domain of tau, and αSyn seeds induce intracellular aggregation of tau.

    “the C-terminal of αSyn can directly interact with the microtubule binding domain of tau [178], and αSyn seeds have been shown to induce intracellular aggregation of tau [179].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [178] Oikawa T, Nonaka T, Terada M, Tamaoka A, Hisanaga S, Hasegawa M. alpha-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly. J Biol Chem. 2016;291:15046–56. source

      Not checked in the free run.

    • cites [179] Waxman EA, Giasson BI. Induction of intracellular tau aggregation is promoted by alpha-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J Neurosci. 2011;31:7604–18. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    αSyn is secreted within exosomes in a calcium-dependent manner and can be taken up by cells via HSPGs.

    “Similar to tau, it has been suggested that αSyn is secreted within exosomes in a calcium-dependent manner [100]. It was further proposed that αSyn can be taken up by cells via HSPGs similar to what has been reported for tau and Aβ [101]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 2010;30:6838–51. source

      Not checked in the free run.

    • cites [101] Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013;110:E3138–47. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP Tg/α-syn KO animals exhibit reduced cholinergic and hippocampal neurodegeneration, less behavioral deficits and increased expression of Rab proteins.

    “APP Tg/α-syn KO animals exhibited reduced cholinergic and hippocampal neurodegeneration, less behavioral deficits and increased expression of Rab proteins [170]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Spencer B, Desplats PA, Overk CR, Valera-Martin E, Rissman RA, Wu C, Mante M, Adame A, Florio J, Rockenstein E, Masliah E. Reducing Endogenous α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci. 2016;36:7971–84. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APOE reduces cellular uptake of Aβ by competing for HSPGs, and the APOE4 isoform limits cellular uptake of αSyn in oligodendrocytes.

    “APOE was shown to reduce cellular uptake of Aβ by competing for HSPGs [148] and specifically the APOE4 isoform limited the cellular uptake of αSyn in oligodendrocytes [149].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [148] Fu Y, Zhao J, Atagi Y, Nielsen HM, Liu CC, Zheng H, Shinohara M, Kanekiyo T, Bu G. Apolipoprotein E lipoprotein particles inhibit amyloid-beta uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener. 2016;11:37. source

      Not checked in the free run.

    • cites [149] Ogaki K, Martens YA, Heckman MG, Koga S, Labbe C, Lorenzo-Betancor O, Wernick AI, Walton RL, Soto AI, Vargas ER, et al. Multiple system atrophy and apolipoprotein E. Mov Disord. 2018. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Membrane-free αSyn multimers, specifically αSyn tetramers, form the largest steady-state pool of intracellular αSyn.

    “Dettmer and co-authors instead postulated that membrane-free αSyn multimers, specifically αSyn tetramers, form the largest steady-state pool of intracellular αSyn [134]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Dettmer U. Rationally Designed Variants of alpha-Synuclein Illuminate Its in vivo Structural Properties in Health and Disease. Front Neurosci. 2018;12:623. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP/αSyn mice have significantly reduced Aβ plaque burden but exacerbated behavioral deficits, more deleterious neuronal cell cycle re-entry, and increased levels of Aβ oligomers, αSyn oligomers and tau pathology.

    “Although the APP/αSyn mice had a significantly reduced Aβ plaque burden, they had exacerbated behavioral deficits, more deleterious neuronal cell cycle re-entry, and increased levels of Aβ oligomers, αSyn oligomers and tau pathology [171].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Khan SS, LaCroix M, Boyle G, Sherman MA, Brown JL, Amar F, Aldaco J, Lee MK, Bloom GS, Lesne SE. Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. Acta Neuropathol. 2018;136:589–605. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αSyn overexpression reduces the size of the reserve- and ready-releasable pools of synaptic vesicles, inhibits post-endocytosis vesicle clustering and attenuates SNARE-mediated exocytosis.

    “αSyn overexpression reduced the size of the reserve- and ready releasable pools of synaptic vesicles, inhibited post-endocytosis vesicle clustering and attenuated SNARE mediated exocytosis [166]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] 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;65:66–79. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The spreading of pathology was previously proposed to result from intra- and intercellular propagation of pathological seeds of tau, Aβ, αSyn and TDP-43 following a prion-like mechanism.

    “The spreading of pathology was previously proposed to result from intra- and intercellular propagation of pathological seeds of tau, Aβ, αSyn and TDP-43 following a prion-like mechanism [204].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Goedert M. NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science. 2015;349:1255555. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The amygdala is heavily regulated by an inhibitory network of cells but primarily responds to glutamate, resulting in secretion of neurotransmitters including acetylcholine, dopamine, serotonin and norepinephrine.

    “Although the amygdala is heavily regulated by an inhibitory network of cells, it primarily responds to glutamate resulting in the secretion of neurotransmitters including acetylcholine, dopamine, serotonin and norepinephrine [214].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] LeDoux J. The amygdala. Curr Biol. 2007;17:R868–74. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuropathological lesions of AD, PD/DLB, and ALS are known to spread through the brain in a rather specific pattern, which serves as a basis for neuropathological staging of disease severity.

    “As aforementioned, the neuropathological lesions of not only AD but also PD/DLB and amyotrophic lateral sclerosis (ALS) are known to spread through the brain in a rather specific pattern, which also serves as a basis for the neuropathological staging of disease severity [203].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501:45–51. source

      Not checked in the free run.

37 of 37

  • The paper relies on this without support.

    The co-occurrence of αSyn pathology with Alzheimer’s disease pathology and the association of cerebrospinal fluid αSyn levels with Alzheimer’s disease-related measures indicate that αSyn contributes to Alzheimer’s disease pathophysiology rather than being an incidental bystander.

    “we speculate that αSyn indeed contributes to the pathophysiology of AD as an underappreciated member of the pathological AD ensemble.”

  • The authors state this as an assumption.

    αSyn primarily exists as an unfolded protein in dynamic equilibrium with smaller pools of membrane-bound αSyn.

    “Many reports have confirmed the widely held assumption that αSyn primarily exists as an unfolded protein in dynamic equilibrium with smaller pools of membrane-bound αSyn”

  • The paper relies on this without support.

    In cell-free, cell and animal models, αSyn fibrils are readily able to catalyze the fibrillation of monomeric αSyn into aggregates of varying toxicity.

    “i) it is widely known that in cell-free, cell and animal models, αSyn fibrils are readily able to catalyze the fibrillation of monomeric αSyn into aggregates of varying toxicity”

  • The paper relies on this without support.

    αSyn can spread to adjacent cells via cell-surface receptors like HSPGs.

    “cell-surface receptors like HSPGs”

  • The paper relies on this without support.

    Numerous clinical studies have documented the presence of αSyn pathology in patients with AD.

    “Numerous clinical studies have by now documented the presence of αSyn pathology in patients with AD”

  • The paper relies on this without support.

    Little attention has been devoted to αSyn as a potential target for AD disease-modification, prevention or cure.

    “little attention has been devoted to αSyn as a potential target for AD disease-modification, prevention or cure.”

  • The paper relies on this without support.

    Strong correlations exist between CSF levels of αSyn and tau in multiple neurodegenerative disorders including AD.

    “the strong correlations found between CSF levels of αSyn and tau in multiple neurodegenerative disorders including AD”

  • The paper relies on this without support.

    Recent data implies that the AD and DLB genetic risk factor APOEε4 may be linked to processes connecting αSyn to the core AD pathological hallmarks, Aβ plaques and NFTs.

    “Importantly, recent data implies that the AD and DLB genetic risk factor APOEε4 may be linked to processes connecting αSyn to the core AD pathological hallmarks, Aβ plaques and NFTs.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Table 2 cohort counts fall short of N=68

    Minor

    The three listed groups sum to 56, leaving 12 of the stated 68 participants unaccounted for.

    Reported 68 · recomputed 56

  • Table 1 cohort counts exceed the stated total

    Minor

    The listed diagnostic groups sum to 361, not the stated N=325.

    Reported 325 · recomputed 361

  • Table 2 gives conflicting AD-DLB comparisons

    Minor

    The same study's findings say DLB patients have lower CSF αSyn than AD patients, then say there is no difference between AD and DLB patients.

3 of 3

The citation lists haven’t been fetched yet

References 214 · Cited by 374

Research works printed but not linked: 3

  1. Lippa CF, Fujiwara H, Mann DMA, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St. George-Hyslop P, et al. Lewy Bodies Contain Altered α-Synuclein in Brains of Many Familial Alzheimer's Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes. Am J Pathol. 1998;153:1365–70. · DOI · Paper page
  2. Logan T, Bendor J, Toupin C, Thorn K, Edwards RH. α-Synuclein promotes dilation of the exocytotic fusion pore. Nat Neurosci. 2017. · DOI
  3. Spencer B, Desplats PA, Overk CR, Valera-Martin E, Rissman RA, Wu C, Mante M, Adame A, Florio J, Rockenstein E, Masliah E. Reducing Endogenous alpha-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci. 2016;36:7971–84. · DOI

Authors
Twohig, D., & Nielsen, H. M.
Affiliations
Stockholm University (SE)
Corresponding author
Nielsen, Henrietta M.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2019-06-11
Volume
14
Issue
1
Pages
23-23
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-019-0320-x
PMC
PMC6558879
OpenAlex
W2952095672
Cited by
374
References
214
Citations by year
2026: 45 · 2025: 63 · 2024: 81 · 2023: 63 · 2022: 49 · 2021: 39 · 2020: 34
FWCI
3.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimer's Association (2015-NIRG-339824)
  • Demensförbundet (2017)
  • Marcus Borgströms Stiftelse (2017)
  • Stiftelsen Olle Engkvist Byggmästare (184-333)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
alpha-synuclein, Alzheimer's disease, amyloid plaques, tau hyperphosphorylation, cerebrospinal fluid biomarkers, APOE ε4, mild cognitive impairment, synucleinopathies, presynaptic proteins, protein structure-function relationship
MeSH terms
Alzheimer Disease, Brain, Humans, tau Proteins, alpha-Synuclein, Plaque, Amyloid, Cognitive Dysfunction

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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