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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Acknowledgements This work was supported by grants from the National Institutes of Health (NIH) to SEL (R01AG044342) and start-up funds from the University of Minnesota Foundation to SEL. We are indebted to the Strom and Moe families for their gift. The Bloom lab was supported by the Owens Family Foundation; the NIH (grant RF1 AG051085 to GSB and NIH pre-doctoral fellowship F31 NS09244401 to SSK); the Alzheimer’s Association (Zenith Fellowship ZEN-16-363266 to GSB); the Cure Alzheimer’s Fund; the University of Virginia’s President’s Fund for Excellence; Webb and Tate Wilson; and the Virginia Chapter of the Ladies Auxiliary of the Fraternal Order of Eagles.
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- Alzheimer’s disease
- Neuronal cell cycle re-entry
- Spatial memory