Soluble α-Synuclein Is a Novel Modulator of Alzheimer's Disease Pathophysiology

Recent evidence has emphasized soluble species of amyloid-beta (A beta) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that A beta, tau, and alpha-synuclein (alpha Syn) can promote each other's aggregation, the potential contribution of soluble alpha Syn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble alpha Syn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble alpha Syn levels were a quantitatively stronger correlate of cognitive impairment than soluble A beta and tau levels. To examine a putative role for alpha Syn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type alpha Syn. The results revealed that an approximate threefold elevation of alpha Syn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble alpha Syn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between A beta/APP and human tau seems to be responsible for the abnormal elevation of soluble alpha Syn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal alpha Syn in AD pathophysiology.