Mechanisms of Resilience to Alzheimer's Disease Neuropathology

摘要 阿尔茨海默病(AD)是最常见和最严重的与年龄相关的神经退行性痴呆 找到解决办法是国家的当务之急。发现保持弹性的个体 尽管存在阿尔茨海默病的神经病理通常与完全有症状的 疾病的不同阶段，表明大脑有一种方法可以避免痴呆症，即使面对阿尔茨海默病。它 因此，了解这种非凡抵抗的机制(S)将揭示 开发一种基于诱导任何人的认知弹性的新的、有效的治疗概念 挑战阿尔茨海默病的神经病理学。考虑到这一目标，我们发现这些脑区的大脑突触 未受影响的个体对有毒的β-淀粉样蛋白(A-)寡聚体和 Tau(一种与AD痴呆发病有关的事件)，这种抵抗力与存在 与AD患者和对照组相比，海马区神经干细胞(NSC)的数量增加 研究对象。虽然这些观察表明持续的神经发生和突触抵抗之间存在联系 损伤淀粉样低聚体，涉及的机制(一个明显的治疗靶点)仍不清楚。基座 关于令人兴奋的新的、令人信服的初步数据，涉及从国家科学委员会特别发布的作为介体的外显体 对于这种现象，在这个项目中，我们将检验NSC来源的外切体呈现突触的假设 抵抗A和tau寡聚体的破坏结合，从而保护记忆障碍。 采用A和tau寡聚体诱导的突触功能障碍和认知功能障碍的体外和体内模型 损伤，在特定目标1中，我们将检验NSC来源的外切体减少突触的假设 淀粉样蛋白低聚物结合的易感性及其功能后果。在具体目标2中，我们将 描述NSC-exosome中存在的与这些效应有关的microRNAs。 在拟议的研究完成后，我们将记录以前未获认可的 神经干细胞外切体介导的突触抵抗A-和tau寡聚体现象及发现 可以促进它的特定miRNAs。鉴于miRNAs对药物开发的翻译价值，这 Discovery将通过说明创新技术的开发目标在该领域产生重大影响 AD的治疗理念以促进突触对有毒寡聚体的抵抗为中心，这是一种策略 如NDAN受试者的存在所表明的那样，预计对人类有效。一个独一无二的合格 已经组建了调查小组，以成功完成这一项目，汇集了 AD分子神经生物学(Taglialatela)，神经干细胞生物学(MICI)，淀粉样蛋白生物化学(Kayed)， MiRNA测序和分析(加宽)、电生理学和动物行为(克里希南)。

ABSTRACT Alzheimer’s disease (AD) is the most common and severe age-associated neurodegenerative dementia for which finding a resolving cure is a pressing national priority. The discovery of resilient individuals who remain cognitively intact despite the presence of AD neuropathology normally associated with a fully symptomatic stages of the disease, suggests that there is a way for the brain to evade dementia even in the face of AD. It follows that understanding the mechanism(s) involved in such extraordinary resistance would reveal targets for the development of a novel, effective therapeutic concept based on inducing cognitive resilience in anyone challenged with AD neuropathology. With this goal in mind, we have discovered that brain synapses in these unaffected individuals are resistant to the disrupting binding of toxic oligomers of both amyloid beta (A) and tau (an event linked to onset of dementia in AD) and that this resistance is associated with the presence of higher numbers of neural stem cells (NSC) in the hippocampus as compared to either AD patients and control subjects. While these observations suggest a link between sustained neurogenesis and synaptic resistance to damaging amyloid oligomers, the involved mechanism (an obvious treatment target) remains unknown. Based on exciting new, compelling preliminary data involving exosomes specifically released from NSC as mediators of this phenomenon, in this project we will test the hypothesis that NSC-derived exosomes render synapses resistant to the disrupting binding of A and tau oligomers and thus protect from memory deficits. Employing both ex vivo and in vivo models of A and tau oligomer-induced synaptic dysfunction and cognitive impairment, in Specific Aim 1 we will test the hypothesis that NSC-derived exosomes reduce synaptic susceptibility to amyloid oligomers binding and its functional consequences. In Specific Aim 2 we will characterize microRNAs present in NSC-exosomes responsible for these effects. At the completion of the proposed studies we will have documented a previously unappreciated phenomenon of synaptic resistance to A and tau oligomers mediated by NSC-exosomes and discovered specific miRNAs that can promote it. Given the translational value of miRNAs for drug development, this discovery will have a substantial impact in the field by illustrating targets for the development of an innovative treatment concept for AD centered on promoting synaptic resistance to toxic oligomers, a strategy expected to be effective in humans as suggested by the existence of NDAN subjects. A uniquely qualified investigative team has been assembled to successfully accomplish this project, bringing together expertise in AD molecular neurobiology (Taglialatela), NSC biology (Micci), biochemistry of amyloid proteins (Kayed), miRNA sequencing and analysis (Widen), electrophysiology and animal behavior (Krishnan).