Is RAGE still a therapeutic target for Alzheimer's disease?

The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in inflammatory disorders, tumor outgrowth, diabetic complications and Alzheimer's disease (AD). RAGE transports circulating amyloid-β toxins across the blood-brain barrier (BBB) into the brain. RAGE-amyloid-β toxin interaction at the BBB leads to oxidative stress, inflammatory responses and reduced cerebral blood flow. Thus, regulating RAGE activity at the BBB and/or within brain could be beneficial to AD patients. Herein, the structure-function relation for RAGE-ligand interaction and the role of RAGE as a potential target in the development of treatments for AD and other RAGE-associated disorders are discussed. Despite recent setbacks in the development of RAGE-based therapies for AD, a new generation of compounds that regulate RAGE activity could be efficacious. Careful studies are needed in rodent and nonrodent animal models of AD with new the generation of RAGE antagonists to ensure safety and efficacy in chronic treatment before clinical trials.