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.
['Kitazawa|Masashi|M|', 'Hsu|Heng-Wei|HW|', 'Medeiros|Rodrigo|R|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D001921:Brain D002460:Cell Line D019327:Copper Sulfate D016207:Cytokines D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D042783:Endothelial Cells D006801:Humans D018836:Inflammation Mediators D026503:Low Density Lipoprotein Receptor-Related Protein-1 D008822:Mice, Transgenic D017628:Microglia D010587:Phagocytosis D046988:Proteasome Endopeptidase Complex D011973:Receptors, LDL D057900:Transcytosis D025521:Tumor Suppressor Proteins
copper phagocytosis LRP1 cytokines Alzheimer’s disease inflammation microglia