Promoting Brain Resilience to Alzheimer's Neuropathology

项目总结/摘要 寻找阿尔茨海默病（AD）的解决方法是一项迫切的关键需求。有充分的共识， 成功的治疗应该针对AD的早期病理事件。其中，突触功能障碍诱导 被认为是AD中最早的关键驱动事件之一， 有吸引力的治疗目标，但仍然缺乏有效的策略。我们的长期目标是帮助发展 增加突触对A β和tau寡聚体的弹性以用于临床治疗的治疗上有用的方法 AD患者的治疗。考虑到这一目标，我们最近报告说， 海马神经干细胞（NSC-exo）使CNS突触对A β寡聚体的破坏性影响具有弹性 通过选定的微RNA（miRNA）货物，一种可能在人类大脑中发挥作用的机制， 具有大量NSC和对A β寡聚体有弹性的突触的老年个体， 尽管CNS存在广泛的AD神经病理学，但仍保持完整。这种弹性机制是否也 有效对抗由tau寡聚体引起的突触破坏-tau寡聚体是发病和 AD的临床进展-尚待确定。因此，本申请的总体目标是评估 NSC（及其释放的外泌体）与增加突触对毒性作用的恢复力之间的联系 tau寡聚体作为衰老的函数，是最强的AD风险因素。基于严格的先前文献报告 和令人信服的初步结果，我们的中心假设是，NSC-exo，通过提供独特的miRNA货物， 使突触对有毒的tau寡聚体具有抗性，并且这种保护机制在衰老过程中由于 有充分证据表明，与年龄相关的NSC损失，使老年大脑更容易受到AD毒性淀粉样蛋白的影响 (and因此更有可能发展为临床表现的AD）。该项目的基本原理是， 确定NSC-exo（及其miRNA）的临床前治疗功效和相关机制 货物）作为老化的函数可能会提供一个强大的科学框架， 对促进突触对AD病理性寡聚体的恢复力的作用。为了实现总体目标， 我们将追求三个具体目标，以评估NSC-exo在促进突触恢复力方面的功效， Tau寡聚体（Aim 1），确定所涉及的miRNA货物及其对关键突触蛋白（Aim 2)并评估衰老对这种保护机制的影响， 常驻NSC及其释放的外来体（Aim 3）。在建议的研究完成后， 期望我们将记录到一种以前未被认识到的突触抵抗现象， NSC-exo介导的毒性寡聚体及其miRNA货物在老化过程中失效。这一发现将说明 目标是开发一种以维持突触为中心的AD创新治疗概念， 在老化环境中对有毒低聚物的抗性，这是一种预期在人类中有效的策略， 这是因为老年人的神经干细胞数量多，突触排斥寡聚体。

PROJECT SUMMARY/ABSTRACT Finding a resolving cure for Alzheimer’s Disease (AD), is an urgent critical need. There is ample consensus that successful treatments should target early pathological events in AD. Among these, synaptic dysfunction induced by oligomers of both A and tau is recognized as one of the earliest key driving events in AD and thus an attractive treatment target, but an effective strategy is still missing. Our long-term goal is to help develop therapeutically useful approaches to increase synaptic resilience to A and tau oligomers for the clinical treatment of AD patients. With this goal in mind, we recently reported that exosomes specifically released by hippocampal neural stem cells (NSC-exo) render CNS synapses resilient to the disruptive impact of A oligomers via selected micro RNA (miRNA) cargoes, a mechanism likely at play in the human brain as suggested by reports of aged individuals with high numbers of NSC and synapses resilient to A oligomers who remain cognitively intact despite the CNS presence of extensive AD neuropathology. Whether such mechanism of resilience is also effective against synaptic disruption brought about by tau oligomers- a recognized major player in the onset and clinical progression of AD- remain to be established. Thus, the overall objective in this application, is to evaluate the link between NSC (and their released exosomes) and increased synaptic resilience to the toxic actions of tau oligomers as a function of aging, the strongest AD risk factor. Based of rigorous previous literature reports and compelling preliminary results, our central hypothesis is that NSC-exo, via delivering unique miRNA cargoes, render synapses resistant to toxic tau oligomers and that such protective mechanism fails during aging owing to the well-documented age-related loss of NSC, leaving the aged brain more vulnerable to the AD toxic amyloids (and therefore more at risk of developing clinically manifest AD). The rationale for this project is that a determination of the preclinical therapeutic efficacy and associated mechanisms of NSC-exo (and their miRNA cargoes) as a function of aging is likely to offer a strong scientific framework whereby a new strategy centered on promoting synaptic resilience to AD pathological oligomers could be developed. To obtain the overall objective, we will pursue three specific aims that will evaluate the efficacy of NSC-exo in promoting synaptic resilience to Tau oligomers (Aim 1), determine the invoved miRNA cargoes and their impact on key synaptic proteins (Aim 2) and evaluate the impact of aging on such protective mechanisms as a function of decreasing numbers of resident NSC and their released exosomes (Aim 3). At the completion of the proposed studies, it is our expectation that we will have documented a previously unappreciated phenomenon of synaptic resistance to toxic oligomers mediated by NSC-exo and their miRNA cargo that fails during aging. This discovery will illustrate targets for the development of an innovative treatment concept for AD centered on sustaining synaptic resistance to toxic oligomers in an aging environment, a strategy expected to be effective in humans as suggested by the existence of aged resilient subjects with high NSC numbers and synapses that reject oligomers.