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

In Alzheimer disease (AD), amyloid beta peptide (A beta) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates A beta-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked A beta binding to the V domain of RAGE and inhibited A beta 40- and A beta 42-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 APP(sw/0) mice overexpressing human A beta-precursor protein, a transgenic mouse model of AD with established A beta pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating A beta 40 and A beta 42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited beta-secretase activity and A beta production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced A beta 40 and A beta 42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APP(sw/0) mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of A beta-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.