| First Author | Khan SS | Year | 2018 |
| Journal | Acta Neuropathol | Volume | 136 |
| Issue | 4 | Pages | 589-605 |
| PubMed ID | 29995210 | Mgi Jnum | J:289241 |
| Mgi Id | MGI:6434707 | Doi | 10.1007/s00401-018-1886-z |
| Citation | Khan SS, et al. (2018) Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. Acta Neuropathol 136(4):589-605 |
| abstractText | alpha-Synuclein (alphaSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble alphaSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted alphaSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by alphaSyn. Overexpression of human wild-type alphaSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-beta oligomers (AbetaOs), alphaSyn 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 alphaSyn 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 alphaSyn decreased extracellular AbetaOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates alphaSyn as an essential mediator of key phenotypes in AD and offers new functional insight into alphaSyn pathophysiology. |
