Copper Exposure Perturbs Brain Inflammatory Responses and Impairs Clearance of Amyloid-Beta.
Copper promotes a toxic buildup of amyloid-beta (Aβ) and neurofibrillary tangle pathology in the brain, and its exposure may increase the risk for Alzheimer's disease (AD). However, underlying molecular mechanisms by which copper triggers such pathological changes remain largely unknown. We hypothesized that the copper exposure perturbs brain inflammatory responses, leading to impairment of Aβ clearance from the brain parenchyma. Here, we investigated whether copper attenuated Aβ clearance by microglial phagocytosis or by low-density lipoprotein-related receptor protein-1 (LRP1) dependent transcytosis in both in vitro and in vivo When murine monocyte BV2 cells were exposed to copper, their phagocytic activation induced by fibrillar Aβ or LPS was significantly reduced, while the secretion of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, were increased. Interestingly, not only copper itself but also IL-1β, IL-6, or TNF-α were capable of markedly reducing the expression of LRP1 in human microvascular endothelial cells (MVECs) in a concentration-dependent manner. While copper-mediated downregulation of LRP1 was proteasome-dependent, the cytokine-induced loss of LRP1 was proteasome- or lysosome-independent. In the mouse model, copper exposure also significantly elevated neuroinflammation and downregulated LRP1 in the brain, consistent with our in vitro results. Taken together, our findings support the pathological impact of copper on inflammatory responses and Aβ clearance in the brain, which could serve as key mechanisms to explain, in part, the copper exposure as an environmental risk factor for AD.
*Molecular and Cell Biology School of Natural Sciences, University of California, Merced, California 95343 Division of Occupational and Environmental Medicine, Department of Medicine, Center for Occupational and Environmental Health (COEH); kitazawa@uci.edu.
Masashi
M
Kitazawa
*Molecular and Cell Biology School of Natural Sciences, University of California, Merced, California 95343.
Heng-Wei
HW
Hsu
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
Rodrigo
R
Medeiros
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D019327:Copper Sulfate / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016207:Cytokines; D018836:Inflammation Mediators; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D046988:Proteasome Endopeptidase Complex; D019327:Copper Sulfate
Alzheimer’s disease; LRP1; copper; cytokines; inflammation; microglia; phagocytosis