Environmental copper exposure and its impact on microglial Abeta clearance

描述(申请人提供)：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，慢性铜暴露对人的晚年生活的影响及其在中枢神经系统中的作用机制尚未完全阐明。虽然它对神经元的直接毒性和与淀粉样β蛋白(Aü)物种的相互作用目前已经被研究，但它对中枢其他非神经细胞的慢性影响被忽视了。我们假设，慢性环境相关铜暴露损害了小胶质细胞吞噬功能和神经炎性反应的激活，促进了Aü物种的病理积聚、突触丧失和认知能力下降。本研究的目的是在活体内确定铜介导的神经胶质活性功能障碍是否促进神经退行性变和AD的神经病理。为了实现我们的目标，我们建议应用两种新的技术来确定慢性铜暴露后体内小胶质细胞和星形胶质细胞特异性转录组的动力学。我们的计划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，以及神经胶质细胞功能障碍导致AD发生和发展的潜在分子机制。

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.