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

阿尔茨海默病(AD)和类似的痴呆症给患者和家庭带来了实质性的挑战， 包括医疗、情感和财政困难。了解基本的分子基础 与AD进展相关的是必须制定有针对性的策略，以便在值得注意的情况下进行干预 认知能力下降会发生在患者身上。神经胶质细胞是大脑中的第一个免疫反应者，据信 影响AD病理，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β蛋白(Aβ)，这是在AD大脑中形成聚集体的主要神经毒性蛋白之一， 已有研究认为，Aβ的胶质细胞清除缺陷可能与其发病或进展有关。 广告。神经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？ 对β的认可和吞噬？最后，一旦β被神经胶质细胞内化，它的命运会是怎样的？ 利用在果蝇中建立的AD模型，我们已经确定Draper受体是一个 抗A-β毒性的新型神经保护分子。Draper是一种高度保守的神经胶质吞噬物 神经胶质吞噬细胞清除凋亡神经元和退化轴突所需的受体。值得注意的是， Draper或哺乳动物同源基因(MEGF10/JEDI)在胶质细胞清除β功能中的作用从未被报道过 在体内进行了探索。在这里，我们表明，胶质细胞拖拉器的丢失导致更大的Aβ积累，加剧 运动缺陷，并进一步缩短寿命，而神经胶质Draper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，依赖Draper的自噬激活 通路可能影响A-β诱导的中枢神经系统功能障碍的进展。因此，我们假设神经胶质细胞 利用Draper受体在成人脑内内化和/或降解神经毒性Aβ多肽 DRAPER活性减弱Aβ诱导的表型。德雷珀激活了几条下游信号通路， 包括改变细胞骨架重塑、自噬和转录(特别是STAT92E和AP-1)。在……里面 目标1，我们将使用遗传和显微镜方法，以及行为分析，来询问已知的 Draper的下游信号效应器决定哪些途径可以防止β积聚、运动 缺陷，并降低寿命。在目标2中，我们将调查德雷珀影响Aβ的可能性 在整个中枢神经系统中传播。更具体地说，我们认为胶质细胞拖拽/自噬促进Aβ 破坏，从而抑制Aβ肽的扩散。使用体内遗传操作和超分辨率 显微镜下，我们将抑制胶质细胞拖曳和自噬途径，以确定β是否更容易在 成人的大脑。这项工作将迅速为Draper/MEGF10如何与AD耦合提供新的分子洞察力 更广泛地说，它将在我们对神经胶质的理解方面提供显著的进步 免疫与阿尔茨海默病以及其他蛋白质病有关。

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.