Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons
Open accessAbstract
α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.
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Reduced α-synuclein increases Aβ deposition in APP mutant mice; increased α-synuclein decreases spatial memory formation, increases neuronal cell cycle dysfunction, and increases specific tau conformational markers.
“For instance, while reduced α-synuclein increases Aβ deposition in APP mutant mice, increased α-synuclein was shown in the same experiment to decrease spatial memory formation, increase neuronal cell cycle dysfunction, and increase specific tau conformational markers (43).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [43]
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α-synuclein in the pathophysiology of Alzheimer’s disease
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- Authors
- 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.
- Affiliations
- University of Virginia (US)
- University of Minnesota (US)
- Corresponding author
- Lesné, Sylvain E.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2018-07-11
- Volume
- 136
- Issue
- 4
- Pages
- 589-605
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6329667
- OpenAlex
- W2856800476
- Cited by
- 41
- References
- 59
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 4 · 2022: 9 · 2021: 9 · 2020: 5 · 2019: 5
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01 AG044342, RF1 AG051085)
- National Institute of Neurological Disorders and Stroke (F31 NS09244401)
- Alzheimer's Association (ZEN-16-363266)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, Alzheimer's disease, APP transgenic mice, amyloid-beta oligomers, amyloid deposition, spatial memory impairment, tau phosphorylation, tau conformation, neuronal cell cycle re-entry, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phosphorylation, Protein Conformation, Amyloid beta-Protein Precursor, tau Proteins, Gene Deletion, Mice, Knockout, Maze Learning, Excitatory Postsynaptic Potentials, Mice, alpha-Synuclein, Primary Cell Culture
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