A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease
Open accessAbstract
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.
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RAGE-mediated reentry or influx of circulating Aβ across the blood-brain barrier is associated with neuroinflammatory response, cerebral blood flow reductions, and blood-brain barrier breakdown.
“which is associated with neuroinflammatory response, CBF reductions, and BBB breakdown (134, 136)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [136]
The Discussion (page unavailable) describes RAGE-mediated entry of circulating Aβ across the BBB. The Results and Discussion also link RAGE inhibition in the mouse model with improved cerebral blood-flow responses and reduced neuroinflammation. But the Introduction (page unavailable) describes BBB breakdown as a possible contributor to peripheral Aβ influx, not as an effect associated with RAGE-mediated influx; the claim's BBB-breakdown link is therefore unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBlocking RAGE at the BBB reduces Aβ reentry into the brain, inhibits neuroinflammation, and improves CBF in a mouse model of AD.
“On the other hand, blocking RAGE at the BBB (134) effectively reduces A 𝛃 reentry into the brain, inhibits neuroinflammation, and improves CBF in a mouse model of AD (134, 136).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [136]
The Results report that blocking RAGE at the BBB inhibited Aβ influx into the brain, while FPS-ZM1 restored cerebral blood-flow responses in aged APPsw/0 mice. The Discussion attributes suppression of neuroinflammation to FPS-ZM1’s actions in the brain as well as at the BBB; the BBB-only blocker was only marginally effective for blood flow. Thus the claim overstates what BBB blockade alone achieved. (LLM, conf=0.88)
Experimental — accuracy not yet measuredUnder pathological conditions, RAGE mediates reentry or influx of circulating Aβ across the blood-brain barrier into the brain.
“Under pathological conditions, RAGE mediates reentry or influx of circulating A 𝛃 across the BBB into the brain, which is associated with neuroinflammatory response, CBF reductions, and BBB breakdown (134, 136)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [136]
Increased RAGE expression likely contributes to circulating amyloid-beta influx, neuroinflammation, and reduced cerebral blood flow in Alzheimer's disease.
“likely contributing to circulating A 𝛃 influx, neuroinflammation, and reduced CBF (134, 136).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [136]
The three RAGE forms bind various ligands with similar affinities, including AGEs and amyloid β peptide.
“The three RAGE forms bind various ligands with similar affinities, including multiple advanced glycation end-products (AGEs) and amyloid β peptide31–37.”
From Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice (2019) · cites this paper as [35]
RAGE is being targeted for inhibition in drug discovery efforts.
“Since both of these are deleterious, pathological effects, RAGE is being targeted for inhibition in drug discovery efforts35.”
From Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice (2019) · cites this paper as [35]
The interaction of Aβ with RAGE causes oxidative stress in neurons, enhances inflammatory responses in microglia, and is involved in reversed transport of Aβ across the BBB in endothelial cells.
“The interaction of Aβ with RAGE causes oxidative stress in neurons, enhances inflammatory responses in microglia, and is involved in reversed transport of Aβ across the BBB in endothelial cells (Deane et al., 2012).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Deane et al., 2012
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- Authors
- 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.
- Affiliations
- University of Rochester Medicine (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-04-02
- Volume
- 122
- Issue
- 4
- Pages
- 1377-1392
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3314449
- OpenAlex
- W2079815081
- Cited by
- 619
- References
- 66
- Citations by year
- 2026: 27 · 2025: 42 · 2024: 42 · 2023: 46 · 2022: 52 · 2021: 54 · 2020: 64 · 2019: 34 · 2018: 43 · 2017: 46 · 2016: 43 · 2015: 43 · 2014: 29 · 2013: 36 · 2012: 17
- FWCI
- 27.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- National Institutes of Health
- National Institute on Aging (R37AG023084, AG029481, R01AG029481)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta, receptor for advanced glycation end products, RAGE inhibitors, FPS-ZM1, blood-brain barrier, microglial activation, neuroinflammation, beta-secretase inhibition, cognitive impairment, cerebral blood flow, disease-modifying therapy
- MeSH terms
- Receptor for Advanced Glycation End Products, Aging, Alzheimer Disease, Animals, Benzamides, Blood-Brain Barrier, Brain, Cerebrovascular Circulation, Cricetulus, Disease Models, Animal, Drug Evaluation, Preclinical, Cricetinae, Humans, Male, Mice, Transgenic, Peptide Fragments, Psychomotor Performance, Receptors, Immunologic, Recombinant Fusion Proteins, Amyloid beta-Peptides, CHO Cells, Neuroprotective Agents, Mice, Amyloid Precursor Protein Secretases, Small Molecule Libraries
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