A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. Deane, R., Singh, I., Sagare, A. P., Bell, R. D., Ross, N. T., LaRue, B., Love, R., Perry, S., Paquette, N., Deane, R. J., Thiyagarajan, M., Zarcone, T., Fritz, G., Friedman, A. E., Miller, B. L., & Zlokovic, B. V. The Journal of Clinical Investigation, 122(4):1377–1392, April, 2012.
doi  abstract   bibtex   
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.
@article{deane_multimodal_2012,
	title = {A multimodal {RAGE}-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of {Alzheimer} disease},
	volume = {122},
	issn = {1558-8238},
	doi = {10.1172/JCI58642},
	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.},
	language = {ENG},
	number = {4},
	journal = {The Journal of Clinical Investigation},
	author = {Deane, Rashid and Singh, Itender and Sagare, Abhay P. and Bell, Robert D. and Ross, Nathan T. and LaRue, Barbra and Love, Rachal and Perry, Sheldon and Paquette, Nicole and Deane, Richard J. and Thiyagarajan, Meenakshisundaram and Zarcone, Troy and Fritz, Gunter and Friedman, Alan E. and Miller, Benjamin L. and Zlokovic, Berislav V.},
	month = apr,
	year = {2012},
	keywords = {Advanced Glycosylation End Product-Specific Receptor, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Animals, Benzamides, Blood-Brain Barrier, CHO Cells, Cerebrovascular Circulation, Cricetinae, Cricetulus, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Male, Mice, Mice, Transgenic, Neuroprotective Agents, Peptide Fragments, Psychomotor Performance, Receptors, Immunologic, Recombinant Fusion Proteins, Small Molecule Libraries, aging, brain},
	pages = {1377--1392}
}
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