Soluble aSyn is a modulator of AD pathophysiology

描述（由申请人提供）：该项目的长期目标是更好地了解α -突触核蛋白（αSyn）可溶性形式在阿尔茨海默病（AD）中的作用。我们最近发表的研究结果表明(i)在缺乏αSyn沉积的情况下，AD大脑中神经元内可溶性αSyn异常升高，（ii）在人类中，可溶性αSyn与认知功能的定量相关性优于可溶性淀粉样蛋白- β (a β)和tau蛋白，(iii) αSyn过表达导致小鼠认知功能障碍。（iv） αSyn的升高导致突触囊泡蛋白的减少和突触囊泡蛋白组成的改变；(v) a β/APP和人tau之间的协同作用似乎是导致转基因小鼠可溶性αSyn异常升高的原因。在这项研究中，我们提出确定可溶性非纤维形式的αSyn是否调节小鼠的认知能力下降，并揭示αSyn可能损害记忆的突触机制。本应用程序的总体目标是确定可溶性αSyn分子(s)的作用及其对AD的相对贡献。总之，我们的观察结果表明，AD可能不是一种双蛋白疾病（即a β和tau），而是a β、tau和可溶性αSyn对神经元突触的三管齐下的攻击。为了验证这一具有挑衅性的假设，我们提出了三个问题：1)从APP小鼠中删除αSyn基因SNCA是否会改善行为、病理和突触囊泡组成？2)在αSyn转基因动物和AD患者的大脑中，哪些形式的可溶性αSyn与认知障碍相关？3)可溶性αSyn物质改变突触前囊泡组成的机制是什么？

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 (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?