Editors' ChoiceNeuroscience

Calming RAGE in Alzheimer’s Disease

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Science Translational Medicine  02 May 2012:
Vol. 4, Issue 132, pp. 132ec75
DOI: 10.1126/scitranslmed.3004203

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of elderly patients worldwide. As AD progresses, the brains of AD patients accumulate aggregates of amyloid β peptide called plaques that kill neurons and result in cognitive dysfunction, memory loss, and dementia. Many studies have tried to inhibit the buildup of amyloid aggregates in the brain with small molecules or antibodies, but the results of clinical trials have been disappointing. Now, Deane et al. have discovered a small-molecule inhibitor of the receptor for advanced glycation end products (RAGE) that blocks amyloid peptide buildup and ameliorates cognitive deficits in a mouse model of AD.

In AD, RAGE is thought to act as a gatekeeper, mediating the influx of circulating amyloid peptide into the brain and regulating its activity in neurons. Previous work suggested that RAGE may be an important therapeutic target, but treatments that targeted RAGE have failed so far because they were unable to pass through the blood brain barrier (BBB) or were too toxic. Deane and colleagues searched through a library of 5000 small molecules to find those that could inhibit the interactions of the amyloid peptide with RAGE and were nontoxic. After identifying several compounds with these characteristics, they then created a second-generation library of 100 compounds that were structurally related and screened them for molecules that could cross the BBB.

This strategy revealed one compound (FPS-ZM1) that could cross the BBB and had activity against RAGE. They tested FPS-ZM1 in a transgenic mouse model of AD and found that it reduced levels of amyloid peptide in the brain and blocked signaling pathways controlling amyloid production. In addition, FPS-ZM1 normalized cerebral blood flow and improved cognitive performance in the AD mouse model.

The work of Deane et al. suggests that blocking RAGE may be a promising strategy for treating AD. The small molecule they identified overcomes two major barriers to clinical translation: It can cross the BBB and has low toxicity. However, further studies in rodents and nonhuman primates will be needed to test the safety and efficacy of this lead compound.

R. Deane et al., A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Invest. 122, 1377–1392 (2012). [PubMed]

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