Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits
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Significance: Alzheimer’s disease (AD) is the most common form of dementia affecting an estimated 5.3 million Americans based on the 2015 Report of the Alzheimer Association. Our current understanding of the pathogenesis of AD suggests that soluble, nonfibrillar forms of amyloid proteins [e.g. amyloid-β, tau, and α-synuclein (αSyn)] may be responsible for impairing cognition and have therefore been advanced to be the most bioactive species in this brain disorder. We sought to determine the potential contribution of αSyn oligomers to AD-associated cognitive decline. We found that selective αSyn oligomers are elevated in AD brains and that genetically elevating oligomeric αSyn in an AD mouse model led to a selective decrease in presynaptic proteins and cognitive performance.
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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 [73]
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 [73]
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RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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RetractedLarson, M. E., Sherman, M. A., Amar, F., Nuvolone, M., Schneider, J. A., Bennett, D. A., Aguzzi, A., & Lesné, S. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1858-12.2012 · Cited by 274 · see citing works
Self-citationRetractedAccumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo.
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RetractedRETRACTED: Soluble α-Synuclein Is a Novel Modulator of Alzheimer's Disease Pathophysiology
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for the Dominantly Inherited Alzheimer Network (DIAN), Twohig, D., Rodriguez-Vieitez, E., Sando, S. B., Berge, G., Lauridsen, C., Møller, I., Grøntvedt, G. R., Bråthen, G., Patra, K., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0624-z · Cited by 68 · see citing works
Matsuo, K., Cheng, A., Yabuki, Y., Takahata, I., Miyachi, H., & Fukunaga, K. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.03.029 · Cited by 43 · see citing works
Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons
Khan, S. S., LaCroix, M., Boyle, G., Sherman, M. A., Brown, J. L., Amar, F., Aldaco, J., Lee, M. K., Bloom, G. S., & Lesné, S. E. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1886-z · Cited by 41 · see citing works
Self-citation
- Authors
- Larson, M. E., Greimel, S. J., Amar, F., LaCroix, M., Boyle, G., Sherman, M. A., Schley, H., Miel, C., Schneider, J. A., Kayed, R., Benfenati, F., Lee, M. K., Bennett, D. A., & Lesné, S. E.
- Affiliations
- University of Minnesota (US)
- Rush University Medical Center (US)
- The University of Texas Medical Branch at Galveston (US)
- Italian Institute of Technology (IT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-05-22
- Volume
- 114
- Issue
- 23
- Pages
- E4648-E4657
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5468636
- OpenAlex
- W2618220838
- Cited by
- 61
- References
- 81
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 14 · 2018: 8 · 2017: 3
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- HHS | NIH | National Institute on Aging (R01AG044342, P30AG10161, R01AG15819)
- University of Minnesota Foundation (4185-9227-14)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS094557)
- 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
- alpha-synuclein oligomers, synapsin, Alzheimer's disease, memory impairment, cognitive decline, presynaptic proteins, transgenic mouse model, presynaptic dysfunction
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cognition, Disease Models, Animal, Humans, Memory Disorders, Mice, Transgenic, Nuclear Proteins, Recombinant Proteins, Solubility, Genes, Tumor Suppressor, Synapsins, Cyclic AMP Response Element-Binding Protein, Protein Structure, Quaternary, Mice, alpha-Synuclein, Nuclear Receptor Subfamily 4, Group A, Member 2
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