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.

项目摘要/摘要 阿尔茨海默病(AD)是一种毁灭性的疾病，有着巨大的未得到满足的医疗需求。很可能有必要 在疾病发展的早期了解、检测和治疗阿尔茨海默病。患者经常表现出异常 神经活动甚至在病理或认知功能衰退之前。淀粉样β蛋白(Ab)和tau可以扰乱神经活动， 而活动可以影响它们的水平，因此异常的神经活动可能是AB和AND的症状和原因 牛磺酸，形成恶性循环。这个项目将调查这样的假设，即异常的神经活动是 阿尔茨海默病的驱动力和易处理的治疗靶点，以及靶向它可以挽救认知 赤字。关于阿尔茨海默病中异常神经活动的致病作用，缺乏直接证据。 更不用说机制了，这是我们理解中的一个重大差距。人类的成像方法分辨率较低， 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 在患者身上使用，使用有限的数据来告知方案，导致有希望但不确定的结果。 这 该项目将使用尖端系统神经科学技术进行单细胞分辨率检查和 大脑的扰动以确定异常神经活动在认知能力下降中的机制作用 阿尔茨海默病小鼠，并逆转它。为了识别异常的单个神经元和网络动力学，双光子 钙离子成像将用于阿尔茨海默病小鼠在疾病进展的认知任务中。这将是 首次对阿尔茨海默病小鼠在认知任务中的单个神经元活动进行纵向研究，以及 第一个终生研究神经活动的人。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过程中激活的神经元。组织- 清除后，将能够在疾病上对整个大脑以及抗体和tau进行3D投影成像 进步。这将发现与Ab和tau平行变化的特定大脑区域、回路和细胞，以及 与认知相关。这将是第一个全脑范围的、依赖活动的投影追踪实验，以及 首次对阿尔茨海默病的解剖连接变化进行纵向研究。测试功能角色 为了恢复认知，单细胞光遗传学将被用来概括或逆转 阿尔茨海默病的活动模式发生了变化，电路将被调制以纠正连接。 将在AD小鼠中使用光遗传学来确定AD治疗是否通过对神经的影响来改善认知 活动。调查员将从指导人员那里接受技术、概念和职业发展培训 斯坦福大学世界级实验室的领先专家团队，为过渡到教员职位做准备。 这项工作将发现阿尔茨海默病的基本机制。它将导致史无前例的，高度的- 解决方案，关于阿尔茨海默病期间神经活动和连接性变化的全面数据 将确定驱动认知能力下降的特定电路、细胞和活动动力学，这将有助于 智能设计新的、精确的和更早的生物标志物、诊断策略和治疗方法。