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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / metabolism
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / prevention & control*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Benzamides / pharmacology
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Benzamides / therapeutic use*
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Benzamides / toxicity
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Blood-Brain Barrier / drug effects
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Brain / drug effects
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Brain / metabolism
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CHO Cells / drug effects
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Cerebrovascular Circulation / drug effects
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Cricetinae
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Cricetulus
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Disease Models, Animal*
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Drug Evaluation, Preclinical
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Humans
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Male
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Mice
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Mice, Transgenic
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use*
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Neuroprotective Agents / toxicity
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Psychomotor Performance / drug effects
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / antagonists & inhibitors*
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Recombinant Fusion Proteins / metabolism
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Small Molecule Libraries
Substances
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Amyloid beta-Peptides
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Benzamides
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FPS-ZM1
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Neuroprotective Agents
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Peptide Fragments
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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Recombinant Fusion Proteins
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Small Molecule Libraries
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Amyloid Precursor Protein Secretases