Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer's disease

Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved in the pathogenesis of Alzheimer's disease (AD). RAGE is a receptor for amyloid beta peptides (A beta), mediates A beta neurotoxicity and also promotes A beta influx into the brain and contributes to A beta aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform, acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain AD development by reducing A beta transport into the brain and A beta production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.