Molecular Targets of A-beta-Induced Synaptic Dysfunction

描述(申请人提供)：阿尔茨海默病(AD)研究的一个中心目标是识别和逆转受影响的大脑系统和神经回路中最早的病理变化。虽然在晚期阿尔茨海默病的大脑中已经记录了大量的结构和生化变化，但引发神经元功能障碍的早期微观事件提供了潜在的更有吸引力的治疗靶点。阿尔茨海默病发病的最初靶点之一是神经元突触。在其早期阶段，AD的特征是非常纯粹的记忆障碍，这被归因于海马区兴奋性突触传递的亚病理性改变。最近的研究有力地支持了错误加工的淀粉样前体蛋白(APP)和A-β沉积参与了AD的早期突触和认知改变。然而，关于暴露于A-β影响突触可塑性的分子机制，或者可以用来抵消异常可塑性的潜在的代偿机制，人们知之甚少。在这项拟议的研究中，我们将定义A-β诱导的突触功能障碍的分子靶点。 一种新认识的改变突触强度的机制是通过内吞作用快速移除突触后受体。我们最近发现，树突棘包含一个与突触后密度相邻但空间上分离的网状蛋白组装和内吞作用区域。此外，我们还发现，突触后内吞作用的蛋白质机制随着年龄的增长而发生功能变化，并可能因暴露于A-β而上调。这些发现为从分子细节上阐明A-β影响兴奋性传递和突触可塑性的机制提供了机会。这些研究将为AD相关突触可塑性改变的细胞生物学机制提供亟需的见解，并将识别可能纠正A-β诱导的突触功能改变的分子信号通路。因此，这项拟议的研究有望为AD相关的记忆丧失和认知障碍开发新的治疗方法。

DESCRIPTION (provided by applicant): A central goal of research in Alzheimer's disease (AD) is the identification and reversal of the earliest pathological changes in affected brain systems and neural circuits. Although numerous structural and biochemical changes have been documented in late-stage AD brains, the early microscopic events that initiate neuronal dysfunction provide potentially more attractive therapeutic targets. Among the initial targets of AD pathogenesis are neuronal synapses. In its earliest phases, AD is characterized by a remarkably pure impairment of memory that has been attributed to 'subpathological' alterations in excitatory synaptic transmission in the hippocampus. Recent studies strongly support the involvement of misprocessed amyloid precursor protein (APP) and A-beta deposition in the early synaptic and cognitive changes of AD. However, little is known about the molecular mechanisms by which exposure to A-beta affects synaptic plasticity, or potential compensatory mechanisms that could be used to counteract aberrant plasticity. In the proposed research, we will define the molecular targets for A-beta-induced synaptic dysfunction. A newly recognized mechanism for changing synaptic strength is the rapid removal of postsynaptic receptors via endocytosis. We have recently found that dendritic spines contain a zone of clathrin assembly and endocytosis adjacent to, but spatially segregated from, the postsynaptic density. Moreover, we have found that the protein machinery for postsynaptic endocytosis is functionally altered by aging and may be upregulated by exposure to A-beta. These findings present an opportunity to clarify in molecular detail the mechanisms by which A-beta influences excitatory transmission and synaptic plasticity. These studies will provide much-needed insight into the cell biological mechanisms that underlie AD-related changes in synaptic plasticity, and will identify molecular signaling pathways that may correct A-beta-induced changes in synaptic function. As such, the proposed research holds promise for the development of new therapeutic approaches for AD-associated memory loss and cognitive deficit.