ABSTRACT
Whereas amyloid-ß (Aß) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to Aß accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing Aß precursor protein (APP), the objective of this study was to elucidate the mechanism of Cu-induced Aß 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 Aß transporter, and higher brain Aß levels. These effects were reproduced by chronic dosing with low levels of Cu via drinking water without changes in Aß 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 Aß 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 Aß 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 Aß levels in the aging brain.
Subject(s)
Amyloid beta-Peptides/metabolism , Brain/drug effects , Copper/pharmacology , Homeostasis/drug effects , Age Factors , Amyloid beta-Peptides/pharmacokinetics , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Blood-Brain Barrier/metabolism , Blotting, Western , Brain/blood supply , Brain/metabolism , Capillaries/drug effects , Capillaries/metabolism , Cell Survival/drug effects , Cells, Cultured , Copper/metabolism , Dose-Response Relationship, Drug , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Iodine Radioisotopes/pharmacokinetics , Low Density Lipoprotein Receptor-Related Protein-1 , Metabolic Clearance Rate , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Time Factors , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
The ability to carry out simultaneous orthogonal exchange chemistries has opened new opportunities for increasing the numerical and structural diversity accessible to Dynamic Combinatorial Chemistry. We present proof-of-concept experiments demonstrating this concept is transferrable to resin-bound DCC, facilitating the generation and analysis of libraries with greater structural diversity.