In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-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 Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 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 Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

RAGE is a key molecule in the onset and sustainment of the inflammatory response. New studies indicate that RAGE might represent a new link between the innate and adaptive immune system. RAGE belongs to the superfamily of Ig cell-surface receptors and is expressed on all types of leukocytes promoting activation, migration, or maturation of the different cells. RAGE expression is prominent on the activated endothelium, where it mediates leukocyte adhesion and transmigration. Moreover, proinflammatory molecules released from the inflamed or injured vascular system induce migration and proliferation of SMCs. RAGE binds a large number of different ligands and is therefore considered as a PRR, recognizing a structural motif rather than a specific ligand. In this review, we summarize the current knowledge about the signaling pathways activated in the different cell types and discuss a potential activation mechanism of RAGE, as well as putative options for therapeutic intervention.

The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed “nutritional immunity.” CP binds Mn ²⁺ and Zn ²⁺ with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn ²⁺ sequestration. The asymmetry of the CP heterodimer creates a single Mn ²⁺ -binding site from six histidine residues, which distinguishes CP from all other Mn ²⁺ -binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn ²⁺ and Zn ²⁺ being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn ²⁺ sequestration. These data establish the importance of Mn ²⁺ sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.