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

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.

Is RAGE still a therapeutic target for Alzheimer's disease?

The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in inflammatory disorders, tumor outgrowth, diabetic complications and Alzheimer's disease (AD). RAGE transports circulating amyloid-ß toxins across the blood-brain barrier (BBB) into the brain. RAGE-amyloid-ß toxin interaction at the BBB leads to oxidative stress, inflammatory responses and reduced cerebral blood flow. Thus, regulating RAGE activity at the BBB and/or within brain could be beneficial to AD patients. Herein, the structure-function relation for RAGE-ligand interaction and the role of RAGE as a potential target in the development of treatments for AD and other RAGE-associated disorders are discussed. Despite recent setbacks in the development of RAGE-based therapies for AD, a new generation of compounds that regulate RAGE activity could be efficacious. Careful studies are needed in rodent and nonrodent animal models of AD with new the generation of RAGE antagonists to ensure safety and efficacy in chronic treatment before clinical trials.

A multimodal RAGE-specific inhibitor reduces amyloid ß-mediated brain disorder in a mouse model of Alzheimer disease.

In Alzheimer disease (AD), amyloid ß peptide (Aß) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aß-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aß binding to the V domain of RAGE and inhibited Aß40- and Aß42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aß-precursor protein, a transgenic mouse model of AD with established Aß pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aß40 and Aß42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited ß-secretase activity and Aß production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aß40 and Aß42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aß-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.