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

项目总结 一个显著的大脑属性是终生存储和检索信息以供学习和记忆的能力。 阿尔茨海默病(AD)破坏了这种功能，并产生了巨大的个人、家庭和 社会影响。这种情况因缺乏治疗疾病的疗法而进一步恶化 相关临床试验连续失败。对这种疾病的不完全了解已经 严重限制了新疗法的发展，需要对AD进行机制研究。突触 失落一直是阿尔茨海默病的一个标志，并与疾病症状显示出最强的相关性。这 这一过程发生在大量神经元死亡和AD诊断之前很久，表明它在 疾病发病机制。然而，突触退变的分子机制仍然存在。 不完全理解。我们的建议旨在通过研究一种新的范式来研究这一过程 这种依赖于Sarm1的机制导致了AD突触丢失。Sarm1是一种新发现的 NAD+水解酶丰富于轴突终末，但其在AD突触变性中的作用是完全的 未知。我们推测Sarm1通过诱导Sarm1在AD的发生和发展中起关键作用。 轴突和突触变性。这一假设是基于我们的初步数据得出的 Sarm1基因敲除显著减轻AD小鼠的突触障碍和认知能力 功能障碍。我们将使用新的小鼠模型、认知测试、生物化学、 电生理学和超分辨率成像。为此，我们集结了一支杰出的、 交互式研究团队，在突触生物学、神经回路、老鼠方面拥有丰富的专业知识 遗传学和AD病理学。我们提出了三个具体目标：1)定义Sarm1在记忆中的作用 阿尔茨海默病小鼠的破坏和疾病进展；2)轴突和突触中Sarm1功能的评估 阿尔茨海默病脑内的变性；3)阐明Sarm1在阿尔茨海默病中作用的分子机制 病理学及其对β-淀粉样蛋白病理学的影响。通过拟议的工作，我们将测试一个 对AD这个长期存在的问题至关重要的全新概念--突触丢失--以及 研究阿尔茨海默病相关神经变性中Sarm1依赖的信号机制。结果是 将推进AD发病机制的现有知识，并为其新的 通过靶向Sarm1信号通路进行治疗。本建议书是根据 发出指明利息的通知(不是PAR-22-093的-AG-21-041)。

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).