Mechanisms of Synaptic Protection in Cognitive Resilence to Alzheimer's Disease Neuropathology

项目摘要/摘要 有充分的科学证据表明，有毒的A和tau寡聚体被认为是主要的神经病理 阿尔茨海默病(AD)中的因素会导致突触衰竭和痴呆症，但也被公认为一些 个体可在没有临床表现的情况下积累显着的AD神经病理。已建立的 这些非痴呆高病理(NDAN)个体的存在表明，如果结合A 特定AMPA和NMDA受体的寡聚体在AD中触发钙离子破坏和突触衰竭，然后 这些受体的药理学或丰度的改变可能是NDAN突触保护的基础。 个人。然而，人们对人类天然谷氨酸受体的药理敏感性知之甚少。 A和tau寡聚体在AD中的作用，或它们在恢复能力中的作用，因为信息主要来自动物研究 AD或蛋白质表达系统的模型。在这里，我们将通过以下方式填补我们当前知识的这一关键空白 阿尔茨海默病患者谷氨酸能信号转导和钙离子异常调节相关突触蛋白的鉴定 这些蛋白的改变是否与NDAN个体的突触保留指标相关，以及 检测A和tau寡聚体是否对NDAN中的人天然突触受体有不同的激活作用 与AD组和对照组比较。目前的提议将检验这样一种假设，即差异 钙离子通透性谷氨酸受体的区域丰度和/或其药效学特征 对寡聚物种的反应将Ndan与AD和对照组区分开来。我们将检验我们的假设 在一个具有严格特征的死后NDAN、AD和年龄匹配的正常认知控制大脑队列中， 使用两种独特而创新的方法：突触膜微移植(MSM)评估 从尸检人脑分离的天然受体复合体的受体电活动，以及 电生理锚定数据集分析(EDA)以识别与受体活性相关的蛋白质。 这个项目的基本原理是确定有毒物质天然靶标的药理敏感性 寡聚体可能提供一个强大的框架，借此可以开发治疗AD的新策略。二 提出了互补的目标。目标1将确定基因表达修改对 人天然谷氨酸钙离子通透性受体的丰度和功能与AD和AD的比较 对照病例，Aim 2将评估A和tau寡聚体激活人类天然突触的效果 NDAN、AD和正常对照的谷氨酸受体。在拟议的研究结束时，我们预计会有 明确了寡聚体在AD患者中触发突触钙离子失调的机制，但在NDAN受试者中不是。 这些结果将为创新的靶向药理学的未来发展奠定基础 促进阿尔茨海默病突触弹性的干预措施是一种具有临床价值的有效治疗方法。

PROJECT SUMMARY/ABSTRACT There is ample scientific evidence that toxic oligomers of A and tau, considered the major neuropathological factors in Alzheimer’s disease (AD) lead to synaptic failure and dementia, but is also well recognized that some individuals can accumulate significant AD neuropathology without clinical manifestations. The established existence of these non-demented with high pathology (NDAN) individuals, suggests that if binding of A oligomers to specific AMPA and NMDA receptors trigger Ca2+ disruption and synaptic failure in AD, then modifications in the pharmacology or abundance of these receptors may underlie synaptic protection in NDAN individuals. However, little is known about the pharmacological sensitivity of human native glutamate receptors to A and tau oligomers in AD, or their role in resilience, as information primarily has come from studies in animal models of AD or protein expression systems. Here we will fill in this critical gap of our current knowledge by identifying the synaptic proteins involved in glutamatergic signaling and Ca2+ dysregulation in AD, evaluating whether modifications of these proteins correlate with metrics of synaptic preservation in NDAN individuals, and determining whether A and tau oligomers differentially activate human native synaptic receptors in NDAN individuals compared to those in AD and controls. The present proposal will test the hypothesis that differences in the regional abundance of Ca2+-permeable glutamate receptors and/or their pharmacodynamics profile in response to oligomeric species distinguishes NDAN from AD and control subjects. We will test our hypothesis in a rigorously characterized cohort of postmortem NDAN, AD, and age-matched normal cognitive control brains, using two unique and innovative approaches: Microtransplantation of Synaptic Membranes (MSM) to evaluate receptor electrical activity of native receptors complexes isolated from autopsy human brain, and Electrophysiologically-anchored Dataset Analysis (EDA) to identify proteins that correlate with receptors’ activity. The rationale for this project is that determining the pharmacological sensitivity of the natural targets of toxic oligomers is likely to offer a strong framework whereby novel strategies to AD therapy can be developed. Two complementary aims are proposed. Aim 1 will identify the impact of gene expression modifications on the abundance and function of Ca2+ permeable human native glutamate receptors in NDAN compared to AD and control cases, and aim 2 will evaluate the efficacy of A and tau oligomers to activate human native synaptic glutamate receptors from NDAN, AD and control cases. At the end of the proposed research we expect to have defined the mechanisms whereby oligomers trigger synaptic Ca2+ dysregulation in AD but not in NDAN subjects. These results will lay the foundations for the future development of innovative target-directed pharmacologic interventions to promote synaptic resilience in AD as a clinically valuable, effective therapeutic approach.