| First Author | Larson ME | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 30 | Pages | 10253-66 |
| PubMed ID | 22836259 | Mgi Jnum | J:186543 |
| Mgi Id | MGI:5432620 | Doi | 10.1523/JNEUROSCI.0581-12.2012 |
| Citation | Larson ME, et al. (2012) Soluble alpha-Synuclein Is a Novel Modulator of Alzheimer's Disease Pathophysiology. J Neurosci 32(30):10253-66 |
| abstractText | Recent evidence has emphasized soluble species of amyloid-beta (Abeta) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Abeta, tau, and alpha-synuclein (alphaSyn) can promote each other's aggregation, the potential contribution of soluble alphaSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble alphaSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble alphaSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Abeta and tau levels. To examine a putative role for alphaSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type alphaSyn. The results revealed that an approximate threefold elevation of alphaSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble alphaSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Abeta/APP and human tau seems to be responsible for the abnormal elevation of soluble alphaSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal alphaSyn in AD pathophysiology. |
