Promoting Brain Resilience to Alzheimer's Neuropathology

项目摘要/摘要 寻找治疗阿尔茨海默病(AD)的解药，是一项迫切而紧迫的需要。有充分的共识认为 成功的治疗应针对AD的早期病理事件。其中，突触功能障碍引起的 通过A和tau的寡聚体被认为是AD中最早的关键驱动事件之一，因此 有吸引力的治疗目标，但仍然缺乏有效的战略。我们的长期目标是帮助发展 临床上提高突触对A和tau寡聚体的韧性的治疗有用的方法 治疗阿尔茨海默病患者。考虑到这一目标，我们最近报道了由 海马神经干细胞增强中枢神经系统突触对寡聚体的破坏作用 通过选定的微型RNA(MiRNA)货物，一种可能在人脑中发挥作用的机制，如报道所述 对A寡聚体有弹性的神经干细胞和突触数量较多的老年人认知能力保持不变 尽管中枢神经系统存在广泛的阿尔茨海默病神经病变，但仍完好无损。这种弹性机制是否也 有效对抗tau寡聚体带来的突触破坏--tau寡聚体是公认的发病和 阿尔茨海默病的临床进展尚待确定。因此，此应用程序的总体目标是评估 神经干细胞(及其释放的外切体)与增加突触对毒素作用的韧性之间的联系 作为衰老的函数，tau寡聚体是AD的最强危险因素。基于之前严谨的文献报道 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寡聚体具有抵抗力，这种保护机制在衰老过程中因 有据可查的与年龄相关的NSC丢失，使老年人的大脑更容易受到AD有毒淀粉样蛋白的影响 (因此更有可能发展为临床表现的阿尔茨海默病)。这个项目的基本原理是 NSC-exo(及其miRNA)的临床前疗效和相关机制的测定 货物)作为老龄化的一种功能，可能会提供一个强有力的科学框架，从而使新的战略以 在促进突触对AD的弹性方面，可以开发病理性寡聚体。为了达到总体目标， 我们将追求三个具体目标来评估NSC-exo在促进突触弹性方面的有效性 Tau寡聚体(AIM 1)，确定开具发票的miRNA货物及其对关键突触蛋白的影响(AIM 2)并评估衰老对这种保护机制的影响，作为减少数量的函数 常驻神经干细胞及其释放的外切体(目标3)。在完成建议的研究后，我们的 预期我们将记录一种以前未被认识到的突触抵抗现象 NSC-exo介导的有毒寡聚体及其在老化过程中失效的miRNA货物。这一发现将说明 以维持突触为中心的AD创新治疗概念的发展目标 在老化环境中对有毒低聚物的抵抗力，这一策略预计将在人类身上有效，因为 提示存在具有高NSC数和拒绝寡聚体的突触的老年弹性受试者。

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.