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 (Ab), mediates Abeta neurotoxicity and also promotes Abeta influx into the brain and contributes to Abeta 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 Abeta transport intothe brain and Abeta production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.
Zhang
Ling
L
Department of Neurology, Zhongda Hospital Affiliated to Southeast University, 210009 Nanjing, China. zhangling9@hotmail.com
Postina
Rolf
R
Wang
Yingqun
Y
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D020780:Matrix Metalloproteinase 9; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human