Environmental copper exposure and its impact on microglial Abeta clearance

环境和职业铜暴露一直被认为是阿尔茨海默病（AD）的环境危险因素之一。然而，慢性铜暴露对晚期生命的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 (β)物种的相互作用，但其对中枢神经系统中其他非神经元细胞的慢性影响一直被忽视。我们假设慢性环境相关的铜暴露会损害小胶质细胞吞噬和神经炎症反应的激活，促进asβ物质的病理积累，突触丧失和认知能力下降。本研究的目的是确定铜介导的神经胶质活性功能损伤是否会促进体内神经退行性变和AD神经病理。为了实现我们的目标，我们建议应用两种新技术来确定体内慢性铜暴露后小胶质细胞和星形胶质细胞特异性转录组动力学。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作用，以及神经胶质功能障碍导致阿尔茨海默病发病和进展的潜在分子机制。

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.