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

• 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
• 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' s Disease; Alzheimer' 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

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）：长期以来，环境和职业铜暴露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）暴露的晚年影响及其在中枢神经系统（CNS）中的作用机制尚未完全阐明。虽然目前研究了其对神经元的直接毒性和与淀粉样蛋白-β（A β）物质的相互作用，但其对CNS中其他非神经元细胞的慢性影响却被忽视了。我们假设，慢性环境相关的铜暴露损害小胶质细胞吞噬作用和神经炎症反应的激活，促进病理性积聚的AAPONS物种，突触丢失和认知能力下降。本研究的目的是确定铜介导的胶质细胞活性功能障碍是否促进体内神经退行性变和AD神经病理学。为了实现我们的目标，我们建议采用两种新的技术来确定小胶质细胞和星形胶质细胞特异性转录组动态慢性铜暴露在体内。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，以及胶质功能障碍导致AD发病和进展的潜在分子机制。