Understanding the degeneration of axon and nerve terminals in Alzheimer's disease and related dementia brain

了解阿尔茨海默病和相关痴呆大脑中轴突和神经末梢的变性

• 批准号: 10661457
• 负责人: Xuelin Lou
• 金额: $ 39万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661457
• 关键词: Abeta synthesis; Acceleration; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Animals; Axon; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Biology; Brain; Clinical Trials; Cognitive; Data; Degenerative Disorder; Dementia; Development; Disease; Disease Progression; Electrophysiology (science); Failure; Feedback; Genetic; Grant; Hydrolase; Image; Imaging Device; Impaired cognition; Interleukin-1 Receptors; Intervention; Knock-out; Knowledge; Learning; Light; Mediating; Memory; Memory Loss; Metabolism; Molecular; Monitor; Mus; Nerve; Nerve Degeneration; Neuroimmune; Neurologic; Neurologic Deficit; Neurons; Onset of illness; Outcome; Pathogenesis; Pathologic; Pathway interactions; Play; Presynaptic Terminals; Process; Proteins; Recycling; Research; Research Personnel; Resolution; Retrieval; Role; Scheme; Senile Plaques; Signal Pathway; Signal Transduction; Specific qualifier value; Sterility; Stress; Symptoms; Synapses; Testing; Vesicle; Work; abeta accumulation; axonal degeneration; beta amyloid pathology; cognitive function; cognitive performance; experimental study; high resolution imaging; improved; in vivo; insight; interest; knockout gene; loss of function; mouse genetics; mouse model; neural circuit; neuroinflammation; neuron loss; neuronal cell body; new therapeutic target; novel; novel strategies; superresolution imaging; tool; translational approach

PROJECT SUMMARY A remarkable brain attribute is a lifelong ability to store and retrieve information for learning and memory. Alzheimer's disease (AD) destroys this function and generates enormous personal, familial, and societal impacts. This situation is further compounded by the lack of disease-modifying therapies and continuous failures of the related clinical trials. An incomplete understanding of the disease has severely limited the development of new treatments, calling for mechanistic research in AD. Synapse loss has been a hallmark of AD and shows the most robust correlation with the disease symptoms. This process occurs long before massive neuron death and AD diagnosis, indicating its central role in disease pathogenesis. However, molecular mechanisms underlying synapse degeneration remain incompletely understood. Our proposal aims to study this process by investigating a novel paradigm in which a sarm1-dependent mechanism contributes to AD synapse loss. Sarm1 is a newly identified NAD+ hydrolase enriched in axonal terminals, but its role in synapse degeneration in AD is entirely unknown. We hypothesize that sarm1 plays a crucial role in AD onset and progression by inducing axon and synapse degeneration. This hypothesis is formulated based on our preliminary data showing that sarm1 gene knockout significantly alleviates AD mice's synaptic disruptions and cognitive dysfunction. We will evaluate this hypothesis using new mouse models, cognitive assays, biochemistry, electrophysiology, and super-resolution imaging. To this end, we have assembled an outstanding, interactive team of investigators with substantial expertise in synapse biology, neurocircuitry, mouse genetics, and AD pathology. We propose three specific aims: 1) define the role of sarm1 in memory disruption and disease progression in AD mice; 2) evaluate sarm1 function in axon and synapse degeneration in AD brains; 3) illustrate molecular mechanisms of sarm1 action in the context of AD pathology and its impact on β-amyloid pathology. Through the proposed work, we will test a fundamentally new concept essential to a long-standing question of AD—synapse loss—and investigate sarm1-dependent signaling mechanisms in AD-associated neurodegeneration. The results will advance the current knowledge on AD pathogenesis and provide critical insights into its novel treatments by targeting the sarm1 signaling pathway. This proposal is submitted in accordance with the Grant Notice to Specify Interest (NOT-AG-21-041 of PAR-22-093).

项目摘要 出色的大脑属性是存储和检索学习和记忆信息的终身能力。 阿尔茨海默氏病（AD）破坏了这一功能，并产生了巨大的个人，家庭和 社会影响。缺乏改良疾病的疗法和 相关临床试验的连续失败。对疾病的不完全了解 严重限制了新疗法的发展，要求在AD中进行机械研究。突触 损失一直是AD的标志，并且显示出与疾病症状最牢固的相关性。这 过程发生在大规模神经元死亡和AD诊断之前，表明其核心作用 疾病发病机理。但是，突触变性的基础机制仍然存在 不完全理解。我们的建议旨在通过研究一个新的范式来研究这一过程 SARM1依赖性机制有助于AD突触损失。 SARM1是新确定的 NAD+水解酶富含轴突末端，但其在AD中的突触变性中的作用完全是 未知。我们假设SARM1在AD发作中起着至关重要的作用 轴突和突触变性。该假设是根据我们的初步数据提出的 SARM1基因敲除极大地减轻了AD小鼠的突触中断和认知 功能障碍。我们将使用新的鼠标模型，认知测定，生物化学，生物化学评估这一假设 电生理学和超分辨率成像。为此，我们组装了一个杰出的 互动团队的研究人员具有突触生物学，神经记录，鼠标的大量专业知识 遗传学和AD病理学。我们提出了三个具体目标：1）定义SARM1在内存中的作用 AD小鼠的破坏和疾病进展； 2）评估轴突和突触中的SARM1功能 广告大脑的变性； 3）在AD的背景下说明了SARM1作用的分子机制 病理及其对β-淀粉样病理学的影响。通过拟议的工作，我们将测试 从根本上讲，对于长期存在的广告问题 - 节日丧失的问题至关重要的新概念 研究与AD相关神经变性中的SARM1依赖性信号传导机制。结果 将促进当前有关AD发病机理的知识，并为其新颖的批判见解 通过靶向SARM1信号通路来处理。该提案根据 赠款通知指定利息（PAR-22-093的NOT-AG-21-041）。