Role of APP in Synaptic Regulation

描述（由申请人提供）：淀粉样蛋白前体蛋白（APP）的蛋白水解裂解产生β -淀粉样肽（A?）。虽然-淀粉样蛋白病理是阿尔茨海默病（AD）的标志，但突触功能障碍被认为在AD的发病机制中起主要作用。因为?我们认为，了解APP及其加工产物在突触功能中的作用机制，并研究A？在APP的背景下是至关重要的。虽然APP的各种神经元和突触活动已被提出，但它们的生理相关性在很大程度上仍未确定。为此，我们制备了APP缺乏的小鼠，并报道APP在海马突触可塑性和学习记忆中发挥功能作用。我们最近创造了一种APP条件敲除小鼠。这些动物的分析表明APP家族蛋白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在突触前和突触后区室中表达，支持APP在突触间的功能性相互作用。我们的提案旨在测试这种跨突触的APP交互模型，破译APP加工产品的活动，包括A？利用最先进的体外技术和生理及疾病相关小鼠模型相结合，确定APP下游靶点。特别是我们配备了新型APP条件敲除小鼠和人源化APP/A？并且具有独特的定位来解决这些关于APP和A？在中央突触中。公共卫生相关性：APP在AD发病机制中起核心作用；突触功能障碍被广泛认为是阿尔茨海默病的主要原因。虽然?一直是AD研究的重点，但它是作为正常APP处理的一部分而产生的，这一点经常被忽视。因此，生理学与发病机制密切相关，而A？同时影响其他APP代谢物和APP介导的途径。我们最近发现APP可能是一种突触粘附蛋白，并且APP家族蛋白对成年神经元的维持至关重要，这为实现对APP病理生理学的基本理解开辟了一个新的和令人兴奋的方向。因此，确定APP在神经元和突触调节中的分子和细胞机制以及研究a ？在APP的背景下，使用生理和疾病相关的小鼠模型系统代表了AD研究的一个新的和急需的领域。我们的研究将全面了解APP在突触调节中的作用，并为阿尔茨海默病的发病机制提供新的认识。

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. PUBLIC HEALTH RELEVANCE: APP plays a central role in AD pathogenesis; synaptic dysfunction is widely accepted as the primary cause of AD. Although A? has been the focus of AD research, it is often overlooked that it is generated as part of normal APP processing. As such, physiology is intimately linked with pathogenesis, and deregulation of A? is expected to simultaneously affect other APP metabolites and APP-mediated pathways. Our recent finding that APP may function as a synaptic adhesion protein and that APP family of proteins is essential for the maintenance of adult neurons open up a new and exciting direction for achieving a fundamental understanding of the pathophysiology of APP. Accordingly, determining the molecular and cellular mechanisms of APP in neuronal and synaptic regulation and investigating the effect of A? in the context of APP using physiological and disease relevant mouse model systems as proposed represent a novel and much needed area of AD research. Our studies will provide a comprehensive understanding of the role of APP in synaptic regulation and reveal new pathogenic insights into Alzheimer's disease.