Retromer deficiency and Alzheimer's disease pathology

描述(申请人提供)：VPS35是逆转聚体的主要成分，对于选择性地从内体到高尔基体回收膜蛋白是必不可少的。VPS35/逆转聚体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，因为在晚发性PD和AD患者中分别发现了VPS35和SorLA基因的突变。因此，研究VPS35/逆转录聚体缺陷如何导致神经退行性变是非常有意义的。在这项提案中，将检验三个假设。第一个假设是，VPS35/逆转录病毒在锥体神经元中的表达对于预防AD相关的神经病理是至关重要的。第二种假说认为，VPS35/逆转录聚体缺陷神经元在BACE1逆行转运过程中受损，从而增加BACE1活性，促进树突状和轴突变性。第三种假说认为，VPS35/逆转录病毒载体缺陷的小胶质细胞对肿瘤坏死因子�家族的细胞因子高度敏感，释放过量的促炎细胞因子，促进脑部炎症和神经变性。这两个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可以建立VPS35/Retmer在防止BACE1和小胶质细胞过度激活方面的新的细胞功能，还可以为AD和PD等神经退行性疾病的发病机制提供新的线索。我们也希望这项研究能为这些疾病的治疗指明新的治疗策略。

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.