| First Author | Deane R | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 4 | Pages | 1377-92 |
| PubMed ID | 22406537 | Mgi Jnum | J:184555 |
| Mgi Id | MGI:5424311 | Doi | 10.1172/JCI58642 |
| Citation | Deane R, et al. (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 122(4):1377-92 |
| abstractText | In Alzheimer disease (AD), amyloid beta peptide (Abeta) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Abeta-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Abeta binding to the V domain of RAGE and inhibited Abeta40- and Abeta42-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 Abeta-precursor protein, a transgenic mouse model of AD with established Abeta pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Abeta40 and Abeta42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited beta-secretase activity and Abeta production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Abeta40 and Abeta42 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 Abeta-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. |
