Abnormal mitochondrial-endolysosomal contacts in AD

项目概要/摘要 阿尔茨海默病（AD）是老年人群中最常见的神经退行性疾病之一。研究 显示载脂蛋白 E (APOE) ε4 同工型对迟发性 AD 的易感性和发病机制的关键影响 （负载）。 APOE 蛋白以异构体依赖性方式调节细胞外斑块形成中的淀粉样蛋白 β (Aβ)。 线粒体缺陷也与 AD 中的 APOE ε4 和 Aβ 风险相关。 APOE ε4 和 Aβ 可能相互作用 调节细胞器间串扰，这证明了对 AD 发病机制中此类串扰的研究是合理的。飞行员 研究发现，与对照组相比，AD 神经元中线粒体和内溶酶体系统之间形成的接触增加 人脑和小鼠模型中的非 AD 对照。此外，还观察到更多的接触 人类 AD APOE ε4 携带者高于 AD APOE ε3 携带者。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 STARD3 是一个重要的介质。这些激动人心的数据 揭示了线粒体-内溶酶体接触的一种新异常，该异常与 APOE ε4 调节的 Aβ 毒性有关 在公元。因此，我们假设 APOE ε4 导致线粒体-内溶酶体相互作用异常增加，并导致线粒体-内溶酶体相互作用异常增加。 通过增强与 STARD3 的相互作用，Aβ 发生软骨易位/积累，从而导致线粒体 零星负荷的功能障碍和神经变性。为了验证这一假设，对线粒体进行了详细检查 体内和体外 AD 模型需要内溶酶体接触。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 对此，我们将努力破译这三个具体目标：1）异常串扰是否以及如何发生—— 线粒体和内溶酶体系统之间导致线粒体缺陷，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，3）潜在机制是否支持治疗 AD 的潜在潜力。该提案将重点关注与 AD 相关的一般散发性 AD 人群的发病机制 常见的 AD 风险 APOE 亚型。重要的是，所提出的新机制也将为发现尚未发现的新机制铺平道路。 常见 AD 人群的未知治疗靶点。

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.