RETRACTED: Soluble α-Synuclein Is a Novel Modulator of Alzheimer's Disease Pathophysiology
Open accessAbstract
Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aβ and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aβ/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.
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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].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [69]
Soluble αSyn and the local concentrations thereof may play an important role in Alzheimer's disease regardless of Lewy-related pathology.
“the results provided by Larson and colleagues [69, 73] suggest that soluble αSyn and the local concentrations thereof may play an important role in AD regardless of LRP.”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [69]
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References 55 · Cited by 128
- Authors
- Larson, M. E., Sherman, M. A., Greimel, S., Kuskowski, M., Schneider, J. A., Bennett, D. A., & Lesné, S. E.
- Affiliations
- University of Minnesota (US)
- United States Department of Veterans Affairs (US)
- Rush University Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-07-25
- Volume
- 32
- Issue
- 30
- Pages
- 10253-10266
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3425439
- OpenAlex
- W2088698513
- Cited by
- 128
- References
- 55
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 14 · 2019: 11 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 14 · 2014: 12 · 2013: 6 · 2012: 3
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Status
- Retracted
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P30-AG 10161, R01 AG15819, R01AG015819, P30AG010161, R00AG031293)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, tau protein, cognitive impairment, spatial reference memory, synaptic vesicles, synaptic vesicle proteins, APP/PS1 mice, Lewy bodies, retraction
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Neurons, Neuropsychological Tests, Temporal Lobe, Amyloid beta-Peptides, tau Proteins, Maze Learning, Nerve Fibers, Unmyelinated, Mice, alpha-Synuclein, Presenilin-1, Cognitive Dysfunction
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