RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA

迟发性阿尔茨海默病(LOAD)的生化特征是AB肽异常升高和tau磷酸化增强。最近，对于跨膜受体从内体循环到跨高尔基网络(Trans-Golgi Network，TGN)非常重要的逆转录复合体活性降低，已被认为与人类患者表达谱负荷的病理学有关。回溯聚合体的重要性 转运到Load得到了几项研究的支持，包括小鼠和果蝇逆转录病毒缺乏的遗传模型，这些模型增加了AP肽的水平，导致神经功能障碍，在果蝇中，广泛的神经退化。缺陷的逆转录聚体运输也抑制了Wnt信号，提示了一条通过糖原合成酶激酶3β(GSKSp)的途径，逆转录聚体可以通过该途径改变tau的磷酸化。我们假设，逆转录分选缺陷是AB肽水平升高和负载中tau磷酸化增加的核心原因，并且调节逆转录转运水平将对神经退行性变产生积极影响。我们将在转基因果蝇模型中测试这一假设，其中人类淀粉样前体蛋白(APP)和淀粉样前体蛋白Li-分泌酶(BACE)或人Tau表达。我们的具体目标是确定将逆转聚体缺陷与神经退行性变联系起来的分子途径，并表征可能促进逆转聚体稳定性的新的相互作用蛋白。

Late-Onset Alzheimer's disease (LOAD) is biochemically characterized by abnormal elevations of AB peptide and increased tau phosphorylation. Recently, reduced activity ofthe Retromer complex, which is important for the recycling of transmembrane receptors from endosomes to the Trans-Golgi Network (TGN), has been implicated in the pathology of LOAD from human patient expression profiling. The importance of retromer trafficking to LOAD is supported by several studies including both mouse and Drosophila genetic models of retromer deficiency, which have increased levels of Ap peptide, neurological deficits, and in the fly, extensive neurodegeneration. Defective retromer trafficking also inhibits Wnt signaling, suggesting a pathway via glycogen synthase kinase 3 beta (GSKSp) through which retromer could alter tau phosphorylation. We hypothesize that defective retromer sorting is central to both elevated AB peptide levels and increased tau phosphorylation in LOAD and that modulating retromer trafficking levels will have a positive impact on neurodegeneration. We will test this hypothesis in transgenic Drosophila models of LOAD where human Amyloid Precursor Protein (APP) and Amyloid Precursor Protein li-secretase (BACE) or human Tau are expressed. Our specific aims are designed to determine the molecular pathway that connects retromer deficiency to neurodegeneration and characterize novel interacting proteins that could promote retromer stability.