Molecular Targets of A-beta-Induced Synaptic Dysfunction

描述（由申请人提供）：阿尔茨海默病（AD）研究的中心目标是识别和逆转受影响的脑系统和神经回路中的最早病理变化。虽然在晚期AD脑中已经记录了许多结构和生化变化，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。AD发病机制的最初靶点是神经元突触。在其早期阶段，AD的特征在于记忆的显著纯损伤，其归因于海马中兴奋性突触传递的“亚病理”改变。最近的研究强烈支持错误加工的淀粉样前体蛋白（APP）和A-β沉积参与AD的早期突触和认知变化。然而，关于暴露于A-β影响突触可塑性的分子机制，或可用于抵消异常可塑性的潜在补偿机制，知之甚少。在拟议的研究中，我们将确定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清除突触后受体。我们最近发现，树突棘包含一个区域的网格蛋白组装和内吞相邻，但空间隔离，突触后密度。此外，我们发现突触后内吞作用的蛋白质机制在功能上会因衰老而改变，并可能因暴露于A-β而上调。这些发现提供了一个机会，澄清在分子细节的机制，A-β影响兴奋性传递和突触可塑性。这些研究将提供急需的深入了解的细胞生物学机制，在突触可塑性的AD相关的变化，并将确定分子信号通路，可能纠正A-β诱导的突触功能的变化。因此，拟议的研究有望为AD相关记忆丧失和认知缺陷开发新的治疗方法。

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.