Retromer deficiency and Alzheimer's disease pathology

描述（由申请人提供）：VPS 35是retromer的主要组分，对于膜蛋白的选择性内体-高尔基体修复至关重要。Vps 35/retromer功能障碍与阿尔茨海默病（AD）以及帕金森病（PD）的发病机制有关，因为Vps 35和SorLA（retromer的货物）基因的突变已分别在晚发性PD和AD患者中被鉴定。因此，研究VPS 35/retromer缺陷如何促进神经变性是相当有趣的。 本提案将检验三个假设。第一个假设是VPS 35/retromer在锥体神经元中的表达对于预防AD相关的神经病理学至关重要。第二个假设是VPS 35/retromer缺陷神经元在BACE 1逆行运输中受损，从而增加BACE 1活性并促进树突和轴突变性。第三个假设是VPS 35/retromer缺陷的小胶质细胞对TNF家族细胞因子高度敏感，释放过量的促炎细胞因子，促进脑炎症和神经变性。这两种假设都得到了我们的出版物和最近的初步研究的支持。我们希望这些研究不仅能建立VPS 35/retromer在预防BACE 1和小胶质细胞过度激活方面的新细胞功能，而且还能为神经退行性疾病（如AD和PD）的发病机制提供新的线索。我们也希望这项研究可以为治疗这些疾病提供新的治疗策略。

DESCRIPTION (provided by applicant): VPS35 is a major component of retromer that is essential for selective endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is implicated in the pathogenesis of Alzheimer's disease (AD) as well as Parkinson's disease (PD), because mutations in Vps35 and SorLA (a cargo of retromer) genes have been identified in the late-onset PD and AD patients, respectively. Thus, it is of considerable interest to investigate how VPS35/retromer deficiency contributes to neurodegeneration. Three hypotheses will be tested in this proposal. The first hypothesis is that VPS35/retromer expression in pyramidal neurons is critical to prevent AD-relevant neuropathology. The second hypothesis is that VPS35/retromer deficient neurons are impaired in BACE1 retrograde trafficking, thus increasing BACE1 activity and promoting dendritic and axonal degeneration. The third hypothesis is that VPS35/retromer deficient microglial cells are hypersensitive to TNF� family cytokines, releasing excessive proinflammatory cytokines and promoting brain inflammation and neurodegeneration. Both hypotheses are supported by our publications and recent preliminary studies. We hope that the proposed studies will not only establish novel cellular functions of VPS35/retromer in preventing hyper-activation of BACE1 and microglia, but also shed new lights into pathogenesis of neurodegenerative disorders, such as AD and PD. We also hope that this research may point to new therapeutic strategies for the treatment of these disorders.