Role of APP in Synaptic Regulation

描述（由申请方提供）：淀粉样前体蛋白（APP）的蛋白水解裂解产生β-淀粉样肽（A？）。虽然β-淀粉样蛋白病理学是阿尔茨海默病（AD）的标志，但突触功能障碍被认为在AD发病机制中起主要作用。自从A？作为APP加工的一部分，我们认为，了解APP及其加工产物在突触功能中的作用机制，研究A？在APP的背景下是至关重要的。尽管已经提出了APP的各种神经元和突触活动，但它们的生理相关性在很大程度上仍未确定。为此，我们产生了APP缺陷的小鼠，并报道了APP在海马突触可塑性和学习记忆中起着功能性作用。我们最近创造了一种APP条件性敲除小鼠。对这些动物的分析表明，APP蛋白家族在神经元存活和突触结构和功能中起着重要作用。有趣的是，APP介导的突触发生活性需要其在突触前和突触后区室中表达，支持APP跨突触的功能性相互作用。我们的提案旨在测试这种跨突触APP相互作用模型，破译APP处理产品的活动，包括A？，在APP介导的突触特性，并确定APP下游的目标，使用最先进的体外技术和生理和疾病相关的小鼠模型的组合。特别是，我们配备了新的APP条件敲除小鼠和人源化APP/A？敲入小鼠和独特的定位，以解决这些基本问题的病理生理APP和A？在中央突触中。

DESCRIPTION (provided by applicant): Proteolytic cleavages of the amyloid precursor protein (APP) generate beta-amyloid peptides (A?). Although beta-amyloid pathology is the hallmark of Alzheimer's disease (AD), synaptic dysfunction is believed to play a primary role in AD pathogenesis. Since A? is produced as part of APP processing, we reasoned that understanding the mechanisms of APP and its processing products in synaptic function, and investigating the effects of A? in the context of APP are of crucial importance. Whereas various neuronal and synaptic activities of APP have been proposed, their physiological relevance remains largely unestablished. To this end, we generated mice deficient in APP and reported that APP plays a functional role in hippocampal synaptic plasticity and learning and memory. We recently created a strain of APP conditional knockout mice. Analysis of these animals demonstrates an essential role for the APP family of proteins in neuronal survival and synaptic structure and function. Intriguingly, APP-mediated synaptogenic activity requires its expression in both pre- and postsynaptic compartments, supporting a functional interaction of APP across synapse. Our proposal is aimed at testing this trans-synaptic APP interaction model, deciphering the activities of APP processing products, including A?, in APP-mediated synaptic property, and identifying the APP downstream targets using a combination of state-of-the-art in vitro technologies and physiological and disease-relevant mouse models. In particular, we are equipped with the novel APP conditional knockout mice and humanized APP/A? knock-in mice and are uniquely positioned to address these fundamental questions concerning the pathophysiology of APP and A? in central synapses.