DESCRIPTION (provided by applicant): The long-term goal of this project is to better understand the contribution of soluble form(s) of alpha-synuclein (αSyn) in Alzheimer's disease (AD). Our recently published findings suggest that (i) intraneuronal soluble αSyn is abnormally elevated in AD brains in absence of deposited αSyn, (ii) soluble αSyn is a quantitatively better correlate of cognitive function than soluble amyloid-beta (Aβ) and tau in humans, (iii) overexpression of αSyn leads to cognitive impairment in mice, (iv) elevation of αSyn leads to decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles and (v) a synergism between Aβ/APP and human tau appears to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. In this study, we propose to determine whether soluble non-fibrillar forms of αSyn are modulating cognitive decline in mice and to unravel the synaptic mechanism by which αSyn might be impairing memory. The overall objective of this application is to identify the role of soluble αSyn molecule(s) and its(their) relative contribution(s) to AD. Altogether, our observations suggest that AD might not be a two-protein disorder (i.e. Aβ and tau) but instead a three-pronged attack of neuronal synapses by Aβ, tau and soluble αSyn. To test this provocative hypothesis, three questions regrouped under three aims are proposed: 1) Does deleting the αSyn gene SNCA from APP mice improve behavior, pathology and synaptic vesicle composition? 2) What form(s) of soluble αSyn is/are associated with cognitive impairment in brains of αSyn transgenic animals and in subjects with AD? 3) What is the mechanism(s) by which soluble αSyn species alter presynaptic vesicle composition?

PUBLIC HEALTH RELEVANCE: Soluble α-synuclein is a modulator of Alzheimer's disease pathophysiology Project Narrative If our hypothesis is correct, Alzheimer's disease (AD) would not be considered a neurological disorder involving two key proteins, i.e. amyloid-β (Aβ) and tau, but instead a disease triggered by abnormal changes in three key proteins: Aβ, tau and α-synuclein (αSyn). In addition, our findings could explain why drugs effective in current AD mouse models, which harbor amyloid plaques without human wild-type tau or wild-type αSyn, do not work in humans.