Journal
ACTA NEUROPATHOLOGICA
Volume 136, Issue 4, Pages 589-605Publisher
SPRINGER
DOI: 10.1007/s00401-018-1886-z
Keywords
Amyloid-beta; alpha-Synuclein; Tau; Alzheimer's disease; Spatial memory; Neuronal cell cycle re-entry
Categories
Funding
- National Institutes of Health (NIH) [R01AG044342]
- University of Minnesota Foundation
- Owens Family Foundation
- NIH [RF1 AG051085, F31 NS09244401]
- Alzheimer's Association [ZEN-16-363266]
- Cure Alzheimer's Fund
- University of Virginia's President's Fund for Excellence
- Virginia Chapter of the Ladies Auxiliary of the Fraternal Order of Eagles
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alpha-Synuclein (alpha Syn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble alpha Syn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted alpha Syn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by alpha Syn. Overexpression of human wild-type alpha Syn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-beta oligomers (A beta Os), alpha Syn 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 alpha Syn 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 alpha Syn decreased extracellular A beta Os, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates alpha Syn as an essential mediator of key phenotypes in AD and offers new functional insight into alpha Syn pathophysiology.
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