Role of APP in Synaptic Regulation

描述(由申请人提供)：淀粉样前体蛋白(APP)的蛋白分解产生β-淀粉样多肽(A？)。虽然β-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。从A开始？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，并研究A？在APP的背景下是至关重要的。尽管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，我们产生了APP缺陷的小鼠，并报道了APP在海马区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条件性基因敲除小鼠。对这些动物的分析表明，APP家族蛋白在神经元生存和突触结构和功能中发挥着重要作用。有趣的是，APP介导的突触生成活动需要在突触前和突触后的隔室表达，支持APP跨突触的功能相互作用。我们的建议旨在测试这种跨突触的APP交互模型，破译APP中介突触特性中包括A？在内的APP处理产品的活动，并结合最先进的体外技术和生理和疾病相关的小鼠模型识别APP下游靶点。特别是，我们配备了新奇的APP条件敲除鼠标和人性化的APP/A？敲入小鼠和独特的定位来解决这些关于APP和A的病理生理的基本问题？在中央突触中。公共卫生相关性：APP在AD发病机制中发挥核心作用；突触功能障碍被广泛认为是AD的主要原因。虽然A？一直是AD研究的重点，但人们往往忽略了它是作为正常应用程序处理的一部分生成的。因此，生理学与发病密切相关，而A？预计会同时影响其他APP代谢物和APP介导的途径。我们最近发现APP可能作为一种突触黏附蛋白发挥作用，APP家族蛋白对成年神经元的维持是必不可少的，这为从根本上理解APP的病理生理开辟了一个新的令人兴奋的方向。因此，确定APP在神经元和突触调节中的分子和细胞机制，并研究A？在APP的背景下，所提出的使用生理和疾病相关的小鼠模型系统代表了AD研究的一个新的和迫切需要的领域。我们的研究将全面了解APP在突触调节中的作用，并揭示阿尔茨海默病的新病因学见解。

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.