Abnormal mitochondrial-endolysosomal contacts in AD

项目摘要/摘要 阿尔茨海默病(AD)是老年人最常见的神经退行性疾病之一。研究 载脂蛋白Eε4亚型在晚发性阿尔茨海默病易感性和发病机制中的关键作用 (加载)。ApoE蛋白以一种异构体依赖的方式调节细胞外斑块形成中的淀粉样β蛋白(Aβ)。 线粒体缺陷也与AD的危险载脂蛋白ε4和Aβ相关。ApoEε4和Aβ的相互作用可能 调节细胞器间串扰，这证明了AD发病机制中这种串扰的研究是合理的。飞行员 研究发现，与AD神经元相比，AD神经元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都是如此。此外，还观察到更多的接触者 人AD载脂蛋白ε4携带者高于AD载脂蛋白ε3携带者。体外研究表明，载脂蛋白E AD风险亚型影响有丝分裂- 溶酶体接触和线粒体Aβ水平，并确定STARD3是一个重要的介体。这些令人兴奋的数据 揭示了一种与载脂蛋白Eε4调节的Aβ毒性有关的线粒体-内溶酶体接触的新异常 在公元后。因此，我们推测，载脂蛋白Eε4导致线粒体-内溶酶体相互作用异常增强，从而导致细胞死亡。 β通过增强与STARD3的相互作用导致线粒体的线粒体易位/积累 散发性负荷时的功能障碍和神经变性。为了验证这一假设，对有丝分裂的详细检查- 需要通过体内和体外AD模型的内溶酶体接触。这项研究的长期目标是追求 异常的细胞器间串扰，可能是线粒体功能障碍和负荷下神经元变性的基础。在……里面 在这方面，将努力破译这三个具体目标：1)异常串扰是否以及如何- 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)载脂蛋白E的相互作用是什么 ε4及其内质粒在这种细胞器间串扰中的β，3)潜在的机制是否支持Thera-4 阿尔茨海默病的潜在价值。该提案将侧重于与以下相关的普通散发性AD人群的发病机制 常见AD风险载脂蛋白E亚型。重要的是，提出的新机制也将为发现一种尚未 普通AD人群的治疗靶点尚未确定。

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.