Amyloid precursor protein control of NMDA receptor signaling

淀粉样蛋白前体蛋白控制 NMDA 受体信号传导

• 批准号: 9976919
• 负责人: STEVEN J TAVALIN
• 金额: $ 41.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976919
• 关键词: APLP1 gene; APLP2 gene; Age-Years; Alzheimer' s Disease; Amino Acids; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavior; Binding; Binding Proteins; Binding Sites; Biochemical; Biophysics; Calcineurin; Calmodulin; Cause of Death; Cell Nucleus; Cells; Cellular Assay; Cleaved cell; Clinical; Cognition; Coupling; Data; Deposition; Development; Disease; Disease Progression; Effectiveness; Electrophysiology (science); Enzymes; Event; Exhibits; Family member; Feedback; Foundations; Functional disorder; Gene Expression; Glutamate Receptor; Image; Impaired cognition; Impairment; In Vitro; Individual; Kinetics; Lead; Learning; Length; Link; Mediating; Memory; Memory Loss; Methods; Microtubule Proteins; Multienzyme Complexes; Mutate; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Nuclear; PPP3CA gene; Pathogenicity; Pathway interactions; Permeability; Personality; Pharmaceutical Preparations; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Physiology; Play; Presenile Alzheimer Dementia; Process; Property; Proteins; Receptor Signaling; Recombinants; Regulation; Role; Senile Plaques; Shapes; Signal Transduction; Site; Source; Surface; Symptoms; Synapses; Synaptic plasticity; System; T-Cell Activation; Techniques; Testing; base; beta secretase; disability; disorder control; early onset; gamma secretase; imaging approach; link protein; neuron development; novel therapeutic intervention; nuclear factors of activated T-cells; protein function; protein protein interaction; receptor; recruit; synaptic function; tau Proteins; treatment strategy; voltage

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.

阿尔茨海默病（AD）的特征在于记忆和认知的进行性下降， 伴随的行为和性格的改变。AD是死亡和残疾的主要原因， 特别是对于65岁以上的人。目前用于治疗AD的药物有限 有效性由于其进行性，疾病过程被认为是在疾病发生之前就已经开始了。 出现临床症状。因此，为了确定新的目标和治疗策略，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），是一种很好的- 被认为是β-淀粉样肽（Aβ）的来源，A β沉积在淀粉样斑块中， 这是该疾病的关键组织病理学标志。APP的内源性功能尚不完全 尽管如此，APP或负责从APP产生Aβ的裂解酶中的突变是已知的 导致家族性AD（FAD）的早期发病。因此，了解APP可能在做什么非常重要 在分裂之前。突触功能障碍被认为是AD进展中最早的事件之一， 因此，突触处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。与突触功能中的作用雅阁，最近的研究表明， APP和APP样蛋白与谷氨酸受体的N-甲基-D-天冬氨酸亚型（NMDAR）相互作用， 增强受体表面表达。NMDAR具有独特的功能，使其能够在以下方面发挥核心作用： 各种形式的突触可塑性，被认为是学习和记忆的基础，以及神经元 发育和神经变性。考虑到这些受体在这些过程中的关键作用， 可以说与AD相关，对APP和APP家族成员赋予的属性的基本理解 在NMDAR信号传导后的蛋白质的表达对于解码该蛋白质在正常生理学和AD中的作用是必需的。 事实上，功能障碍的突触到核信号传导可能在AD中普遍存在。根据初步数据，我们 相信APP内与FAD连锁突变相关的特定区域对APP的能力至关重要， 及其家族成员，不仅调节NMDAR，而且使NMDAR启动下游信号传导。 目的1将生物化学地检查该区域的特性，并测试FAD连锁突变对细胞内的影响。 APP对这些性能使用在体外和细胞测定。目标2将使用电生理技术， 检查APP及其家族成员是否调节NMDAR功能以及FAD连锁突变的能力 改变NMDAR活性。Aim 3将使用基于成像的细胞分析来检查APP和 其家族成员控制下游NMDAR介导的细胞核信号传导， APP中的突变改变了NMDAR介导的核信号传导的强度。总的来说，这些研究将揭示 一种有助于NMDAR内源性调节的新途径，可能导致功能障碍 AD中的信号。