Environmental copper exposure and its impact on microglial Abeta clearance

环境铜暴露及其对小胶质细胞 Abeta 清除的影响

基本信息

批准号：
8930156
负责人：
Masashi Kitazawa
金额：
$ 15.9万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
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：
2014-09-19 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930156
关键词：
Abeta clearance Adverse effects Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Astrocytes Binding Brain Cells Cessation of life Cholesterol Cholesterol Homeostasis Chronic Cognition Copper Data Deposition Development Diet Disease Elderly Environment Environmental Risk Factor Functional disorder Gene Expression Profile Generations Genes Genetic Predisposition to Disease Genotype Goals Health Heavy Metals Homeostasis Human Impaired cognition Impairment Inflammatory Late Onset Alzheimer Disease Life Link Mediating Metal exposure Microglia Molecular Mus Nerve Degeneration Neuraxis Neuroglia Neurons Occupational Onset of illness Pathology Phagocytosis Population Production RNA Sequences Regulatory Pathway Risk Risk Factors Running Synapses Techniques Testing Therapeutic Toxic effect abeta accumulation cell type cholesterol trafficking functional disability genetic risk factor genome-wide genome-wide analysis high risk immunoregulation in vivo insight mind control mouse model neuroinflammation neuropathology neurotoxicity novel prevent response tau Proteins transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Environmental and occupational copper exposure has long been considered one of the environmental risk factors for Alzheimer's disease (AD). However, the late life impact of the chronic copper (Cu) exposure and its mechanisms of action in the central nervous system (CNS) have not been fully elucidated. While its direct toxicity on neurons and interaction to amyloid-beta (Aß) species are currently been studied, its chronic impact on other non-neuronal cells in the CNS has been overlooked. We hypothesize that a chronic environmentally-relevant Cu exposure impairs the activation of microglial phagocytosis and neuroinflammatory responses, promoting a pathological buildup of Aß species, synaptic loss and cognitive decline. The objective of this study is to determine whether the copper-mediated functional impairment of glial activity promotes neurodegeneration and AD neuropathology in vivo. To achieve our goal, we propose to apply two novel techniques to determine microglia- and astrocyte-specific transcriptome dynamics following chronic Cu exposure in vivo. Our proposed project will uncover the critical pathogenic impact of Cu exposure on microglia, astrocytes and neuroinflammation, and the underlying molecular mechanism by which glial dysfunction leads to the onset and progression of AD in a temporal manner.

描述（由申请人提供）：环境和职业铜暴露长期以来一直被认为是阿尔茨海默病 (AD) 的环境风险因素之一，然而，慢性铜 (Cu) 暴露及其作用机制对晚年的影响。中枢神经系统 (CNS) 尚未完全阐明，虽然目前正在研究其对神经元的直接毒性以及与淀粉样蛋白 (Aß) 的相互作用，但其对中枢神经系统中其他非神经元细胞的长期影响已得到研究。我们忽视了，长期与环境相关的铜暴露会损害小胶质细胞吞噬作用和神经炎症反应，促进 Aß 物种的病理性积累、突触丧失和认知能力下降。本研究的目的是确定铜介导的功能是否存在。神经胶质细胞活性受损会促进体内神经变性和 AD 神经病理学。为了实现我们的目标，我们建议应用两种新技术来确定慢性铜暴露后小胶质细胞和星形胶质细胞特异性的转录组动态。我们提出的项目将揭示铜暴露对小胶质细胞、星形胶质细胞和神经炎症的关键致病影响，以及神经胶质功能障碍导致 AD 发生和进展的潜在分子机制。