RAGE: the beneficial and deleterious effects by diverse mechanisms of actions

Abstract

Receptor for advanced glycation endproducts (RAGE) is a transmembrane protein that belongs to the immunoglobulin superfamily. RAGE is expressed ubiquitously-high in lung and moderate to low in a wide range of cells-in a tightly regulated manner at various stages of development. RAGE is a pattern recognition receptor that binds to multiple ligands, including amphoterin, members of the S100/calgranulin family, the integrin Mac-1, and amyloid β-peptide (Aβ). RAGE-ligand engagement effects the activation of diverse cascades that initiate and stimulate chronic stress pathways and repair, depending on the ligand, environment, and developmental stage. Further, RAGE-ligand interaction and the consequent upregulation of RAGE through a positive feedback loop are often associated with various diseases, including vascular disease, diabetes, cancer, and neurodegenerative disease. It is unknown how RAGE mediates these events, but such phenomena appear to be linked to the inflammatory response. In this review, we summarize the findings on RAGE from published reports and ongoing studies. Also, the implication of RAGE in Alzheimer disease, the most common neurodegenerative disease in the elderly population, will be discussed, with a focus on Aβ-RAGE interactions with regard to signaling pathways and their impact on cellular activity.

Fig. 1.. Isoforms of RAGE, with the variable domains in different colors. RAGE isoforms are generated from splice variants (Ding and Keller, 2005; Kalea et al., 2009; Yonekura et al., 2003) or proteolysis by metalloprotease 9 and γ-secretase cleavage (Galichet et al., 2008; Raucci et al., 2008; Zhang et al., 2008). fRAGE, full-length RAGE; ΔN RAGE, N-truncated forms of RAGE; esRAGE, endogenous secretory RAGE; DN RAGE, dominant-negative RAGE; cRAGE, cleaved RAGE; TD, transmembrane domain; CT, cytosolic tail.

Fig. 2.. Complexity of signal trans-duction pathways induced by RAGE- ligand engagement. See main text for details and references. RAGE binds to many ligands and acti-vates diverse signal transduction pathways in different cell types.

Fig. 3.. Schematic of RAGE functions in the BBB. RAGE mediates Aβ transcytosis, Aβ-induced NF-κB activation, and monocyte/macrophage migra-tion across the BBB (Deane et al., 2003; Giri et al., 2000; Mackic et al., 1998). TJ, tight junction.