Retromer deficiency and Alzheimer's disease pathology

描述（由申请人提供）：VPS35是逆转录酶的主要成分，对于膜蛋白的选择性内体到高尔基体的检索至关重要。VPS35/逆转录酶的功能障碍与阿尔茨海默病（AD）和帕金森病（PD）的发病机制有关，因为VPS35和SorLA（一种逆转录酶）基因的突变已分别在晚发性PD和AD患者中被发现。因此，研究VPS35/逆转录酶缺乏如何导致神经退行性变是非常有意义的。本提案将测试三个假设。第一种假设是VPS35/逆转录物在锥体神经元中的表达对于预防ad相关的神经病理至关重要。第二种假设是VPS35/retromer缺陷神经元在BACE1逆行运输中受损，从而增加BACE1活性，促进树突和轴突变性。第三种假设是VPS35/逆转录酶缺陷的小胶质细胞对TNF家族细胞因子过敏，释放过多的促炎细胞因子，促进脑炎症和神经退行性变。我们的出版物和最近的初步研究都支持这两种假设。我们希望所提出的研究不仅能建立VPS35/逆转录物在防止BACE1和小胶质细胞超激活方面的新细胞功能，还能对AD和PD等神经退行性疾病的发病机制提供新的认识。我们也希望这项研究可以为这些疾病的治疗提供新的治疗策略。

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.