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 阿尔茨海默氏病（AD）是一种毁灭性的疾病，具有巨大的未满足医疗需求。可能有必要 在疾病发育中较早地了解，检测和治疗阿尔茨海默氏病。患者经常表现出异常 神经活动甚至在病理或认知下降之前。淀粉样蛋白β（AB）和TAU可以扰动神经活动， 活动和活动可能影响其水平，因此异常的神经活动既是AB的症状，也是原因 tau，形成一个美好的周期。该项目将调查以下假设，即异常神经活动是主要的 阿尔茨海默氏病的驱动力和可拖动治疗靶点，而目标可以挽救认知 缺陷。缺乏直接证据表明异常神经元活性在阿尔茨海默氏病中的病因作用， 更不用说机制，这是我们理解的显着差距。人类成像方法的分辨率低， 人类研究不能使用精确的扰动来测试直接原因和作用。然而，刺激疗法 使用有限的数据来通知方案，用于患者，从而产生了有希望的但尚无定论的结果。 这 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下降中的机理作用 阿尔茨海默氏病小鼠，并将其逆转。要识别异常的单神经和网络动力学，2-Photon 在疾病进展方面的认知任务期间，CA2+成像将用于阿尔茨海默氏病小鼠。这会 成为认知任务期间阿尔茨海默氏病小鼠中单神经元活动的首个纵向研究， 神经元活性的首次终身研究。发现基于活动的解剖连通性变化，活动 - 依赖性神经元投影标记将用于在学习和回忆过程中激活的神经元标记。组织- 清算将使3D的整个大脑的项目以及AB和Tau的疾病成像 进展。这将发现特定的大脑区域，电路和细胞在与AB和TAU平行发生变化的情况下变化 与认知相关。这些将是第一个大脑范围的，活动依赖性投影追踪实验，并且 关于阿尔茨海默氏病解剖连通性变化的首次纵向研究。测试功能角色 为了恢复异常活动和恢复认知，单细胞光遗传学将用于概括或逆转 阿尔茨海默氏病的活动模式发生了变化，电路将被调制以纠正连通性。 AD小鼠将使用光遗传学来确定AD疗法是否通过对中性的影响来改善认知 活动。调查人员将从心理上获得技术，概念和职业发展培训 斯坦福大学世界一流实验室领先的专家团队为过渡到教师职位做准备。 这项工作将发现阿尔茨海默氏病的基本机制。这将导致前所未有的高级 解决方案，关于阿尔茨海默氏病神经活动变化和连通性变化的全面数据 将确定驱动认知能力下降的特定电路，细胞和活动动态，这将有助于告知 新的，精确和早期的生物标志物，诊断策略和治疗性治疗的智能设计。