title: A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.
abstract: 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 APPsw/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 APPsw/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.
authors.affiliation: Center of Neurodegenerative and Vascular Brain Disorders, University of Rochester, Rochester, New York, USA.
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: Itender
authors.initials: I
authors.lastname: Singh
authors.forename: Abhay P
authors.initials: AP
authors.lastname: Sagare
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bell
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Ross
authors.forename: Barbra
authors.initials: B
authors.lastname: LaRue
authors.forename: Rachal
authors.initials: R
authors.lastname: Love
authors.forename: Sheldon
authors.initials: S
authors.lastname: Perry
authors.forename: Nicole
authors.initials: N
authors.lastname: Paquette
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Deane
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Thiyagarajan
authors.forename: Troy
authors.initials: T
authors.lastname: Zarcone
authors.forename: Gunter
authors.initials: G
authors.lastname: Fritz
authors.forename: Alan E
authors.initials: AE
authors.lastname: Friedman
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Miller
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D016229:Amyloid beta-Peptides; D001549:Benzamides; C572629:FPS-ZM1; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases