Receptors for Advanced Glycation End Products (RAGE): Promising Targets Aiming at the Treatment of Neurodegenerative Conditions

Abstract: Advanced glycation end products (AGEs) are compounds formed after the non-enzymatic addition of reducing sugars to lipids, proteins, and nucleic acids. They are associated with the development of various clinical complications observed in diabetes and cardiovascular diseases, such as retinopathy, nephropathy, diabetic neuropathy, and others. In addition, compelling evidence indicates that these molecules participate in the progression of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Multiple cellular and molecular alterations triggered by AGEs that could alter homeostasis have been identified. One of the main targets for AGE signaling is the receptor for advanced glycation end-products (RAGE). Importantly, this receptor is the target of not only AGEs, but also amyloid β peptides, HMGB1 (high-mobility group box-1), members of the S100 protein family, and glycosaminoglycans. The activation of this receptor induces intracellular signaling cascades that are involved in pathological processes and cell death. Therefore, RAGE represents a key target for pharmacological interventions in neurodegenerative diseases. This review will discuss the various effects of AGEs and RAGE activation in the pathophysiology of neurodegenerative diseases, as well as the currently available pharmacological tools and promising drug candidates.