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

突触保护在阿尔茨海默氏病认知恢复中的机制

• 批准号: 10361401
• 负责人: Agenor Limon
• 金额: $ 44.27万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361401
• 关键词: AMPA Receptors; Ablation; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid; Animal Model; Automobile Driving; Autopsy; Binding; Brain; Caring; Clinical; Clinical Trials; Cognitive; Communication; Complex; Data; Data Set; Dementia; Development; Electrophysiology (science); Fostering; Foundations; Future; Gene Expression; Genetic; Glutamate Receptor; Glutamates; Goals; Health; Human; Individual; Inferior; Intervention; Ions; Knowledge; Lead; Literature; Mediating; Mind; Mission; Modification; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Parietal Lobe; Pathology; Patients; Permeability; Persons; Pharmacodynamics; Pharmacology; Post-Translational Protein Processing; Proteins; Public Health; Publishing; Research; Role; Signal Transduction; Synapses; Synaptic Membranes; Synaptic Receptors; System; Testing; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; Work; base; case control; cognitive control; cohort; disorder control; effective therapy; efficacy evaluation; glutamatergic signaling; improved; innovation; mind control; neuropathology; non-demented; novel; novel strategies; preservation; protein expression; receptor; resilience; response; societal costs; synaptic failure; synaptic function; tau Proteins; tau aggregation; therapeutically effective; treatment center

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.

项目摘要/摘要 有充分的科学证据表明，A和Tau的有毒低聚物被认为是主要的神经病理学 阿尔茨海默氏病（AD）的因素导致突触衰竭和痴呆 个人可以在没有临床表现的情况下积累明显的AD神经病理学。已建立 这些非痴呆的高病理（NDAN）的存在，表明如果A的结合 特定AMPA和NMDA受体的低聚物触发Ca2+​​ AD中的破坏和突触失败，然后 这些受体的药理学或抽象的修饰可能是NDAN突触保护的基础 个人。然而，对人类天然谷氨酸受体的药物敏感性知之甚少 由于信息主要来自动物的研究 AD或蛋白质表达系统的模型。在这里，我们将通过 确定与谷氨酸能信号传导和Ca2+失调有关的合成蛋白，评估 这些蛋白质的修饰是否与Ndan个体突触保存的指标相关，并且 确定A和Tau低聚物是否会不同地激活Ndan中人类天然突触受体 与广告和对照中的人相比。本提案将检验差异的假设 在Ca2+可渗透谷氨酸受体和/或其药效学的区域抽象中 对低聚物种的反应将NDAN与AD和对照对象区分开。我们将检验我们的假设 在严格特征的验尸ndan中，AD和年龄匹配的正常认知控制大脑， 使用两种独特而创新的方法：突触膜的微移植（MSM）来评估 从尸检人脑分离的天然受体复合物的受体电活动，以及 电生理学的数据集分析（EDA）识别与受体活性相关的蛋白质。 该项目的理由是确定有毒自然靶标的药理敏感性 低聚物可能会提供一个强大的框架，从而可以开发出新的广告疗法策略。二 提出了完全目标。 AIM 1将确定基因表达修饰对 与AD相比 控制案例和AIM 2将评估A和Tau低聚物激活人类天然突触的效率 来自NDAN的谷氨酸接收器，AD和控制案例。在拟议的研究结束时，我们期望 定义了寡聚物触发AD中的合成CA2+失调的机制，但在NDAN受试者中却没有。 这些结果将为未来的创新目标导向药理学的发展奠定基础 干预措施以促进AD中的突触弹性作为一种临床上有价值，有效的治疗方法。