Soluble aSyn is a modulator of AD pathophysiology

描述(申请人提供)：本项目的长期目标是更好地了解可溶性α-突触核蛋白(α)在阿尔茨海默病(AD)中的作用。我们最近发表的研究结果表明：(I)在缺乏沉积的αSyn的情况下，AD脑中神经元内的可溶性αSyn异常升高；(Ii)在人类中，可溶性αSyn在数量上比可溶性淀粉样β蛋白(A？)和tau更能反映认知功能；(Iii)αSyn的过度表达导致小鼠认知障碍；(Iv)αSyn的上调导致选定的突触小泡蛋白减少，突触小泡的蛋白质组成发生变化；(V)在转基因小鼠中，Aü/APP与人tau之间的协同作用似乎是导致可溶性αSyn异常升高的原因。在这项研究中，我们建议确定可溶的非纤维形式的α同步蛋白是否正在调节小鼠的认知能力下降，并揭示α同步蛋白可能损害记忆的突触机制。本应用的总体目标是确定可溶性αSyn分子(S)在AD中的作用及其相对贡献(S)。综上所述，我们的观察表明，AD可能不是一种双蛋白紊乱(即A？和tau)，而是A？、tau和可溶性α突触对神经元突触的三管齐下的攻击。为了验证这一挑衅性假说，我们提出了三个问题：1)从APP小鼠中删除αSYN基因SNCA是否能改善行为、病理和突触小泡组成？2)什么形式的可溶性αSYN(S)与αSYN转基因动物和AD受试者的脑认知障碍有关？3)可溶性αSYN物种改变突触前小泡组成的机制(S)是什么？

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 (Aß) 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 Aß/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. Aß and tau) but instead a three-pronged attack of neuronal synapses by Aß, 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?