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 (A) 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 A 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.
Environmental Cu exposure may increase the risk for Alzheimer's disease in later life. We will study how chronic environmental Cu exposure triggers Alzheimer's disease neuropathology, such as amyloid-beta (A) plaque deposition, neuronal death and cognitive decline in a mouse model of the disease. Findings from this project will provide key involvement of environmental risk factors on the onset of the disease and potential therapeutic strategies to treat or prevent Alzheimer's disease among people who are at high risk.
|Hsu, Heng-Wei; Bondy, Stephen C; Kitazawa, Masashi (2018) Environmental and Dietary Exposure to Copper and Its Cellular Mechanisms Linking to Alzheimer's Disease. Toxicol Sci 163:338-345|
|Lim, Siok Lam; Tran, Diana Nguyen; Zumkehr, Joannee et al. (2018) Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology. Glia 66:2700-2718|
|Kitazawa, Masashi; Hsu, Heng-Wei; Medeiros, Rodrigo (2016) Copper Exposure Perturbs Brain Inflammatory Responses and Impairs Clearance of Amyloid-Beta. Toxicol Sci 152:194-204|