Abnormal mitochondrial-endolysosomal contacts in AD

项目概要/摘要 阿尔茨海默病（Alzheimer's disease，AD）是老年人群中最常见的神经退行性疾病之一。研究 载脂蛋白E（APOE）ε4亚型在晚发性AD的易感性和发病机制中具有重要作用 （加载）。APOE蛋白以亚型依赖性方式调节细胞外斑块形成中的淀粉样蛋白β（Aβ）。 线粒体缺陷也显示与AD中的风险APOE ε4和Aβ相关。APOE ε4和Aβ的相互作用可能 调节细胞器间的串扰，这证明了在AD发病机制中对这种串扰的研究是合理的。试点 一项研究发现，与AD神经元相比，AD神经元中线粒体和内溶酶体系统之间形成的接触增加， 非AD对照，在人脑和小鼠模型中。此外，还观察到， 人AD APOE ε4携带者比AD APOE ε3携带者更明显。体外研究表明，APOE AD风险亚型影响线粒体， 内溶酶体接触和线粒体Aβ水平，并确定STARD 3作为重要的介质。这些激动人心的数据 揭示了一种新的线粒体-内溶酶体接触异常，与APOE ε4调节的Aβ毒性相关 在AD中。因此，我们假设APOE ε4引起异常增加的线粒体-内溶酶体相互作用和线粒体-内溶酶体相互作用。 通过增强与STARD 3的相互作用，导致线粒体Aβ易位/蓄积， 功能障碍和神经退行性变。为了验证这一假设，对水龟的详细检查- 需要通过体内和体外AD模型进行内溶酶体接触。本研究的长期目标是追求 异常的细胞器间串扰，可能是LOAD中线粒体功能障碍和神经元变性的基础。在 在这方面，努力将努力破译这三个具体目标：1）是否和如何异常串扰是- 线粒体和内溶酶体系统之间的相互作用导致线粒体缺陷，2）APOE相互作用的作用是什么 ε4及其内体货物Aβ在这种细胞器间串扰中的作用，3）潜在的机制是否支持治疗， AD的潜在危险。该建议将重点放在一般散发性AD人群的发病机制， 常见AD风险APOE同种型。重要的是，所提出的新机制也将为发现一种尚未发现的 常见AD人群的未表征治疗靶点。

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders among the aged population. Studies showed the critical impacts of apolipoprotein E (APOE) ε4 isoform on susceptibility and pathogenesis of late-onset AD (LOAD). APOE proteins modulate amyloid beta (Aβ) in extracellular plaque formation in an isoform dependent manner. Mitochondrial deficits were also shown associated with risk APOE ε4 and Aβ in AD. The interplay of APOE ε4 and Aβ likely modulates the inter-organelle crosstalk, which justifies the investigation into such crosstalk in AD pathogenesis. The pilot study found increased contacts formed between mitochondria and endolysosomal system in AD neurons compared to non-AD controls, both in human brain and the mouse model. Furthermore, many more contacts were observed among human AD APOE ε4 carriers than in AD APOE ε3 carriers. In vitro studies showed APOE AD risk isoform affected the mito- endolysosomal contacts and mitochondrial Aβ levels and identified STARD3 as an important mediator. These exciting data unveiled a novel abnormality in mito-endolysosomal contacts, which was associated with APOE ε4 regulated Aβ toxicity in AD. Therefore, we hypothesized that APOE ε4 caused abnormally increased mito-endolysosome interaction and mi- tochondrial translocation/accumulation of Aβ through enhanced interaction with STARD3 which led to mitochondrial dysfunction and neurodegeneration in sporadic LOAD. To test this hypothesis, the detailed examination of the mito- endolysosomal contact by in vivo and in vitro AD models is required. The long-term goal of this study is the pursuit of abnormal inter-organelle crosstalk that likely underlies mitochondrial dysfunction and neuronal degeneration in LOAD. In this regard, the efforts will strive to decipher these three specific aims: 1) whether and how the abnormal crosstalk be- tween mitochondria and endolysosomal system causes mitochondrial deficits, 2) what is the role of the interplay of APOE ε4 and its endosomal cargo Aβ in such inter-organelle crosstalk, 3) whether the underlying mechanism supports a thera- peutic potential for AD. The proposal will focus on the pathogenesis in general sporadic AD population associated with common AD risk APOE isoform. Importantly, the proposed novel mechanism will also pave the road for discovery of a yet uncharacterized therapeutic target for common AD population.