Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance

Whereas amyloid-beta (A beta) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to A beta accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing A beta precursor protein (APP), the objective of this study was to elucidate the mechanism of Cu-induced A beta accumulation in brains of normal mice and then to explore Cu's effects in a mouse model of Alzheimer's disease. In aging mice, accumulation of Cu in brain capillaries was associated with its reduction in low-density lipoprotein receptor-related protein 1 (LRP1), an A beta transporter, and higher brain A beta levels. These effects were reproduced by chronic dosing with low levels of Cu via drinking water without changes in A beta synthesis or degradation. In human brain endothelial cells, Cu, at its normal labile levels, caused LRP1-specific down-regulation by inducing its nitrotyrosination and subsequent proteosomal-dependent degradation due in part to Cu/cellular prion protein/LRP1 interaction. In APP(sw/0) mice, Cu not only down-regulated LRP1 in brain capillaries but also increased A beta production and neuroinflammation because Cu accumulated in brain capillaries and, unlike in control mice, in the parenchyma. Thus, we have demonstrated that Cu's effect on brain A beta homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma. These findings should provide unique insights into preventative and/or therapeutic approaches to control neurotoxic A beta levels in the aging brain.