Investigating the Role of Draper/MEGF10 in Alzheimer's Disease

阿尔茨海默病（AD）和类似的痴呆给患者和家庭带来了实质性的挑战， 包括医疗情感和经济困难了解基本的分子基础 与AD进展相关的疾病，必须制定有针对性的策略， 患者的认知能力下降。神经胶质细胞是大脑中的第一个免疫反应细胞， 影响AD病理学，尽管分子和细胞细节仍不清楚。健康的神经胶质细胞可以 有效地吞噬淀粉样蛋白-β（Aβ），其是在AD脑中形成聚集体的主要神经毒性蛋白之一， 并且已经提出，胶质细胞对Aβ的清除缺陷可能有助于脑缺血的发生或进展， AD.胶质细胞如何清除大脑中的Aβ？控制神经胶质细胞的分子和信号通路是什么 Aβ的识别和吞噬最后，一旦Aβ被神经胶质细胞内化，它的命运是什么？ 使用一个在果蝇中建立的AD模型，我们已经鉴定了德雷珀受体作为一个与AD相关的受体。 抗Aβ诱导毒性的新型神经保护分子。德雷珀是一种高度保守的胶质细胞吞噬 神经胶质吞噬细胞清除凋亡神经元和变性轴突所需的受体。特别是 德雷珀或哺乳动物直系同源物（MEGF 10/Jedi）在胶质细胞清除Aβ功能中的作用从未被研究过。 在体内探索。在这里，我们发现神经胶质德雷珀的丧失导致更大的Aβ积聚，加剧了 运动缺陷，并进一步减少寿命，而神经胶质德雷珀的激活逆转了这些分子和 行为表型我们的初步工作还表明，Draper依赖的自噬激活 这些通路可能影响Aβ诱导的CNS功能障碍的进展。因此，我们假设神经胶质细胞 利用德雷珀受体内化和/或降解成人大脑中的神经毒性Aβ肽，并且 德雷珀活性减弱Aβ诱导的表型。德雷珀激活了几条下游信号通路， 包括改变的细胞骨架重塑、自噬和转录（特别是STAT 92 E和AP-1）。在 目的1，我们将使用遗传和显微镜方法，以及行为测定，以询问已知的 德雷珀的下游信号传导效应物，以确定哪些途径保护Aβ蓄积，运动 缺陷和寿命缩短。在目标2中，我们将研究德雷珀影响Aβ的可能性 在CNS中传播。更具体地说，我们认为胶质细胞德雷珀/自噬促进Aβ 破坏，从而抑制Aβ肽扩散。使用体内基因操作和超分辨率 在显微镜下，我们将抑制神经胶质德雷珀和自噬途径，以确定Aβ是否更容易传播， 成人大脑这项工作将迅速为德雷珀/MEGF 10如何与AD偶联提供新的分子见解 进展，更广泛地说，将为我们理解胶质细胞如何 免疫与AD以及其他蛋白质病相关。

Alzheimer's disease (AD) and similar dementias present substantive challenges to patients and families, including medical, emotional, and fiscal hardships. Understanding the basic molecular underpinnings associated with AD progression is imperative to develop targeted strategies to intervene before notable cognitive decline occurs in patients. Glial cells, the first immune responders in the brain, are believed to influence AD pathology, although the molecular and cellular details are still unclear. Healthy glial cells can efficiently engulf amyloid-beta (Aβ), one of the major neurotoxic proteins that forms aggregates in the AD brain, and it has been proposed that defects in glial clearance of Aβ may contribute to the onset or advancement of AD. How do glia clear Aβ in the brain? What are the molecules and signaling pathways that govern glial recognition and engulfment of Aβ? Finally, what is the fate of Aβ once it has been internalized by glial cells? Using a well-established AD model in Drosophila melanogaster, we have identified the Draper receptor as a novel neuroprotective molecule against Aβ-induced toxicity. Draper is a highly conserved glial engulfment receptor required for glial phagocytic clearance of apoptotic neurons and degenerating axons. Notably, the role of Draper or the mammalian orthologs (MEGF10/Jedi) in glial clearance of Aβ function have never been explored in vivo. Here, we show that loss of glial Draper results in greater Aβ accumulation, exacerbates locomotor defects, and further reduces lifespan, while activation of glial Draper reverses these molecular and behavioral phenotypes. Our preliminary work also suggests that Draper-dependent activation of autophagy pathways may influence the progression of Aβ-induced CNS dysfunction. Thus, we hypothesize that glial cells utilize the Draper receptor to internalize and/or degrade neurotoxic Aβ peptides in the adult brain and that Draper activity attenuates Aβ-induced phenotypes. Draper activates several downstream signaling pathways, including altered cytoskeletal remodeling, autophagy, and transcription (specifically, STAT92E and AP-1). In Aim 1, we will use genetic and microscopy methods, as well as behavioral assays, to interrogate known downstream signaling effectors of Draper to determine which pathways protect against Aβ accumulation, motor defects, and reduced longevity. In Aim 2, we will investigate the possibility that Draper influences Aβ propagation throughout the CNS. More specifically, we propose that glial Draper/autophagy promotes Aβ destruction, thereby inhibiting Aβ peptide spreading. Using in vivo genetic manipulations and super resolution microscopy, we will inhibit glial Draper and autophagy pathways to determine if Aβ propagates more readily in the adult brain. This work will rapidly offer new molecular insight into how Draper/MEGF10 is coupled to AD progression and, more broadly, will provide a significant advancement in our understanding of how glial immunity is linked AD, as well as other proteinopathies.