Amyloid precursor protein control of NMDA receptor signaling

阿尔茨海默病(AD)的特征是记忆力和认知能力进行性下降， 随之而来的行为和个性的改变。AD是导致死亡和残疾的主要原因， 特别是对65岁以上的个人。目前治疗阿尔茨海默病的药物有限 有效性。由于疾病的渐进性质，人们认为疾病过程早在疾病发生之前就开始了。 出现临床症状。因此，为了确定新的目标和治疗战略，必须更好地 了解与AD相关的蛋白质的生理功能。淀粉样前体蛋白(APP)，很好地- 被认为是沉积在淀粉样斑块中的β-淀粉样多肽(Aβ)的来源，A 该病的主要组织病理学特征。APP的内生功能还不完全 了解，但APP或裂解酶中负责从APP产生Aβ的突变是已知的 导致家族性早发阿尔茨海默病(FAD)。因此，了解应用程序可能在做什么是很重要的 在其乳沟之前。突触功能障碍被认为是AD进展中最早的事件之一，并且 因此，突触上APP的存在可能预示着AD中由于其 过度和/或功能失调的处理。最近的研究表明，与突触功能相一致的是， APP和APP样蛋白与N-甲基-D-天冬氨酸受体亚型(NMDAR)相互作用 增强受体表面表达。NMDAR具有独特的功能，使它们能够在 各种形式的突触可塑性，被认为是学习和记忆的基础，也是神经元的基础 发育和神经退化。鉴于这些受体在这些过程中的关键作用，这些过程都是 可以说与AD相关，对APP和APP家族成员赋予的属性有基本的了解 在NMDAR上，信号是必不可少的，以解码该蛋白在正常生理和AD中的作用。 事实上，功能失调的突触到核的信号可能在阿尔茨海默病中普遍存在。根据初步数据，我们 相信APP中与FAD相关的突变相关的特定区域对APP的能力至关重要， 不仅调节NMDARs，而且还启动NMDARs的下游信号传导。 目标1将对该区域的特性进行生化检查，并测试FAD连锁突变对 APP使用体外和细胞分析对这些特性进行研究。目标2将使用电生理技术来 检查APP及其家族成员是否调节NMDAR功能和FAD连锁突变的能力 在应用程序内更改NMDAR活动。AIM 3将使用基于成像的细胞分析来检查APP和 它的家族成员控制着NMDAR介导的下游信号传递到细胞核以及FAD是否连接 APP的突变改变了NMDAR介导的核信号的强度。总的来说，这些研究将揭示 一条有助于NMDARs内源性调节的新途径，可能是功能障碍的基础 AD中的信令。

Alzheimer’s disease (AD) is characterized by a progressive decline in memory and cognition, with concomitant alterations in behavior and personality. AD represents a leading cause of death and disability, particularly for individuals over 65 years of age. Current medications for treatment of AD have limited effectiveness. Due to its progressive nature, it is thought that disease processes are initiated well before the onset of clinical symptoms. Thus, in order to define new targets and treatment strategies, it is essential to better understand the physiological functions of proteins linked to AD. Amyloid precursor protein (APP), is well- recognized to serve as the source of the β-amyloid peptide (Aβ) that becomes deposited in amyloid plaques, a key histopathological hallmark of the disease. The endogenous functions of APP remain incompletely understood, yet mutations in either APP or cleaving enzymes responsible for generating Aβ from APP are known to cause familial forms of AD (FAD) with early onset. Thus, it is important to understand what APP may be doing prior to its cleavage. Synaptic dysfunction is thought to be one of the earliest events in AD progression, and consequently the presence of APP at synapses likely foretells the critical functions that are lost in AD due to its excessive and/or dysfunctional processing. In accord with a role in synaptic function, recent studies indicate that APP and APP-like proteins interact with the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) to enhance receptor surface expression. NMDARs have unique features that enable them to play central roles in various forms of synaptic plasticity that are thought to underlie learning and memory, as well as in neuronal development and neurodegeneration. Given the pivotal role of these receptors in these processes, which are all arguably relevant to AD, a fundamental understanding of the properties APP and APP-family members endow upon NMDAR signaling is essential in order to decode the role of this protein in normal physiology and in AD. Indeed, dysfunctional synapse to nucleus signaling may be prevalent in AD. Based on preliminary data, we believe that a specific region within APP, associated with FAD-linked mutations, is critical for the ability of APP, and its family members, to not only regulate NMDARs, but also for NMDARs to initiate downstream signaling. Aim 1 will biochemically examine the properties of this region and test the impact of FAD-linked mutations within APP on these properties using in vitro and cellular assays. Aim 2 will use electrophysiological techniques to examine whether APP and its family members regulate NMDAR function and the ability of FAD-linked mutations within APP to alter NMDAR activity. Aim 3 will use imaging-based cellular assays to examine whether APP and its family members control downstream NMDAR-mediated signaling to the cell nucleus and whether FAD-linked mutations in APP alters the strength of NMDAR-mediated nuclear signaling. Collectively, these studies will reveal a new pathway contributing to the endogenous regulation of NMDARs, which may underlie dysfunctional signaling in AD.