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大脑系统和神经回路的早期病理变化。尽管在晚期阿尔茨海默病大脑中已经记录了许多结构和生化变化，但早期引发神经元功能障碍的微观事件提供了潜在的更有吸引力的治疗靶点。阿尔茨海默病发病机制的初始靶点是神经元突触。在其早期阶段，阿尔茨海默病的特征是明显的纯粹的记忆损伤，这被归因于海马兴奋性突触传递的“亚病理性”改变。最近的研究强烈支持错误加工的淀粉样蛋白前体蛋白（APP）和a - β沉积参与阿尔茨海默病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，我们知之甚少。在本研究中，我们将确定a- β诱导的突触功能障碍的分子靶点。

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.