Evaluation of rage isoforms, ligands, and signaling in the brain

Since the identification of the receptor for advanced glycosylation end products (RAGE) in 1992, there have been tremendous strides made in our understanding of the role RAGE receptors play in a variety of physiological and pathological processes. Despite such progress, several fundamental aspects of RAGE expression and RAGE function remain largely unanswered. In particular, while multiple forms of the RAGE receptor are known to exist, little is known with regards to how these different isoforms of the RAGE receptor work together to mediate RAGE signaling. For example, some forms of the RAGE receptor may promote deleterious feed-forward pathways, while others may serve to inhibit deleterious activation of the RAGE receptor. Additionally, important questions remain with regards to the intracellular domain of the full-length RAGE receptor, and the specifics surrounding how intracellular signaling pathways become activated via the RAGE family of receptors. The focus of this review is to address each of these important issues, as well as other key aspects of RAGE biology, and discuss how they are important for both our understanding of the physiological and pathological roles of RAGE signaling within the brain.