Retromer deficiency and Alzheimer's disease pathology

逆转录酶缺乏与阿尔茨海默病病理学

基本信息

批准号：
8708256
负责人：
WEN-CHENG XIONG
金额：
$ 30.92万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708256
关键词：
Address Age Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid Amyloid beta-Protein Precursor Autopsy Brain Cell physiology Chronic Clinical Trials Cognitive deficits Defect Deficiency Diseases Dementia Dendrites Dendritic Spines Deposition Disease Encephalitis Endosomes Exhibits Family Functional disorder Genes Glutamates Goals Golgi Apparatus Health Heterozygote Hippocampus (Brain)Inflammation Inflammatory Interneurons Late Onset Alzheimer Disease Learning Mediating Membrane Proteins Memory MicroRNAs Microglia Morphology Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Parkinson Disease Pathogenesis Pathologic Pathology Patients Peptides Phenotype Presenile Alzheimer Dementia Proteins Publications Research Resistance Retrieval Risk Factors Signal Transduction Slice Swelling Synapses TNFSF11 gene Testing Tg2576 Tumor Necrosis Factor-alpha Vacuolar Protein Sorting axonal degeneration beta-site APP cleaving enzyme 1 cytokine hippocampal pyramidal neuron interest morris water maze mutant neuropathology neurotransmission novel novel therapeutics prevent secretase selective expression small hairpin RNA trafficking treatment strategy young adult

项目摘要

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 TNFα 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.

描述（由适用提供）：VPS35是反逆转的主要组成部分，对于选择性内体至高尔基膜的检索至关重要。 VPS35/缩回剂的功能障碍在阿尔茨海默氏病（AD）以及帕金森氏病（PD）的发病机理中实现，因为在晚期PD和AD患者中，分别鉴定出VPS35和Sorla（替补剂）基因的突变。这是有趣的是，研究VPS35/retromer缺乏症如何促进神经变性。该提案将检验三个假设。第一个假设是，锥体神经元中的VPS35/缩回表达对于预防与AD相关的神经病理学至关重要。第二个假设是，在BACE1逆行运输中，VPS35/缩回缺乏神经元受损，从而增加了BACE1活性并促进树突状和轴突变性。第三个假设是，VPS35/逆转录者缺乏小胶质细胞对TNFα家族细胞因子过敏，释放过多的促炎细胞因子并促进脑感染和神经变性。这两个假设得到我们的出版物和最近的初步研究的支持。我们希望所提出的研究不仅能在防止Bace1和小胶质细胞过度激活中建立VPS35/retromer的新细胞功能，而且还将新的光芒放到神经退行性疾病的发病机理中，例如AD和PD。我们还希望这项研究可以指出治疗这些疾病的新治疗策略。