Identifying the mechanistic role of and reversing aberrant neural activity in Alzheimer's Disease

识别阿尔茨海默病中异常神经活动的机制作用并逆转

• 批准号: 10740789
• 负责人: Theodore Terence Ho
• 金额: $ 12.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740789
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Anatomy; Antibodies; Brain; Brain region; Cells; Clinical; Cognition; Cognitive; Cognitive deficits; Compensation; Data; Development; Disease; Disease Progression; Exhibits; Faculty; Head; Human; Image; Impaired cognition; Intelligence; Label; Learning; Light; Link; Longitudinal Studies; Maps; Medical; Memory; Mentors; Microscopy; Modeling; Mus; Neurons; Neurosciences; Pathology; Patients; Pattern; Phase; Play; Positioning Attribute; Preparation; Protocols documentation; Research Personnel; Resolution; Role; Stains; Symptoms; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Training; Universities; Virus; Work; career development; clinically relevant; cognitive performance; cognitive task; design; diagnostic strategy; early detection biomarkers; experimental study; human imaging; imaging modality; improved; mouse model; neural; neural stimulation; optogenetics; prospective; protein aggregation; recruit; skills; tau Proteins; tau aggregation; temporal measurement; therapeutic target; two-photon

Project Summary/Abstract Alzheimer’s Disease (AD) is a devastating disease with enormous unmet medical need. It is likely necessary to understand, detect, and treat Alzheimer’s Disease earlier in disease development. Patients often exhibit aberrant neural activity even before pathology or cognitive decline. Amyloid-beta (Ab) and tau can perturb neural activity, and activity can affect their levels, thus aberrant neural activity may be both a symptom and cause of Ab and tau, forming a vicious cycle. This project will investigate the hypothesis that aberrant neural activity is a primary driver of and tractable therapeutic target for Alzheimer’s Disease, and that targeting it can rescue cognitive deficits. There is a lack of direct evidence on the causative role of aberrant neural activity in Alzheimer’s Disease, let alone the mechanisms, a significant gap in our understanding. Human imaging methods have low resolution, and human studies cannot use precise perturbations to test direct cause and effect. Yet, stimulation therapies are used on patients, using limited data to inform protocols, resulting in promising but inconclusive results. This project will use cutting-edge systems neuroscience techniques to conduct single-cell resolution examination and perturbation of the brain to determine the mechanistic role of aberrant neural activity in cognitive decline in Alzheimer’s Disease mice, and to reverse it. To identify aberrant single-neuron and network dynamics, 2-photon Ca2+ imaging will be used in Alzheimer’s Disease mice during cognitive tasks over disease progression. This will be the first longitudinal study of single-neuron activity in Alzheimer’s Disease mice during cognitive tasks, and the first lifelong study of neural activity. To discover activity-based anatomical connectivity changes, activity- dependent neuron projection labeling will be used to label neurons activated during learning and recall. Tissue- clearing will enable imaging of projections across the entire brain in 3D, along with Ab and tau, over disease progression. This will discover specific brain regions, circuits, and cells that change in parallel to Ab and tau and correlate with cognition. These will be the first brain-wide, activity-dependent projection tracing experiments, and the first longitudinal study of anatomical connectivity changes in Alzheimer’s Disease. To test the functional role of aberrant activity and to restore cognition, single-cell optogenetics will be used to recapitulate or reverse the activity patterns changed in Alzheimer’s Disease, and circuits will be modulated to correct connectivity. Optogenetics will be used in AD mice to determine if AD therapies improve cognition through effects on neural activity. The investigator will receive technical, conceptual, and career development training from a mentoring team of leading experts in world-class labs at Stanford University in preparation for transition to a faculty position. This work will discover fundamental mechanisms of Alzheimer’s Disease. It will result in unprecedented, high- resolution, comprehensive data on changes in neural activity and connectivity during Alzheimer’s Disease that will identify the specific circuits, cells, and activity dynamics that drive cognitive decline, which will help inform intelligent design of new, precise, and earlier biomarkers, diagnostic strategies, and therapeutic treatments.

项目总结/摘要 阿尔茨海默病（AD）是一种具有巨大未满足的医疗需求的毁灭性疾病。可能有必要 了解，检测和治疗阿尔茨海默病的早期疾病发展。患者经常表现出异常的 甚至在病理或认知能力下降之前就开始了神经活动。β淀粉样蛋白（Ab）和tau可以干扰神经活动， 活动可以影响它们的水平，因此异常的神经活动可能既是Ab的症状，也是Ab的原因， 形成恶性循环。这个项目将调查的假设，异常的神经活动是主要的 阿尔茨海默病的驱动因素和易处理的治疗靶点，并且靶向它可以挽救认知能力。 赤字缺乏关于异常神经活动在阿尔茨海默病中的致病作用的直接证据， 更不用说机制了，这是我们理解上的一个重大差距。人类成像方法分辨率低， 人类研究不能使用精确的扰动来测试直接的因果关系。然而，刺激疗法 用于患者，使用有限的数据来告知协议，导致有希望但不确定的结果。 这 该项目将使用尖端的系统神经科学技术进行单细胞分辨率检查， 干扰大脑，以确定异常神经活动在认知能力下降中的机制作用， 为了识别异常的单神经元和网络动力学， Ca 2+成像将在阿尔茨海默病小鼠中在疾病进展的认知任务期间使用。这将 是第一个在认知任务中对阿尔茨海默病小鼠单神经元活动的纵向研究， 第一个终生研究神经活动的项目为了发现基于活动的解剖连接变化，活动- 依赖神经元投射标记将用于标记在学习和回忆期间激活的神经元。组织- 清除将使整个大脑的投影在3D成像，沿着与抗体和tau，超过疾病 进展这将发现与Ab和tau平行变化的特定大脑区域、回路和细胞， 与认知相关。这将是第一个全脑范围的、依赖于活动的投射追踪实验， 第一次纵向研究阿尔茨海默病的解剖连接变化。测试功能角色 异常活动和恢复认知，单细胞光遗传学将用于重演或逆转 活动模式在阿尔茨海默病中改变，电路将被调节以纠正连接。 光遗传学将用于AD小鼠，以确定AD疗法是否通过对神经元的影响来改善认知。 活动研究者将接受来自导师的技术、概念和职业发展培训 斯坦福大学世界级实验室的顶尖专家团队，准备过渡到教师职位。 这项工作将发现阿尔茨海默病的基本机制。它将导致前所未有的，高- 关于阿尔茨海默病期间神经活动和连接变化的全面数据， 将确定驱动认知下降的特定电路，细胞和活动动力学，这将有助于告知 智能设计新的、精确的和早期的生物标志物、诊断策略和治疗方法。