RAGE and Alzheimer's disease: a progression factor for amyloid-beta-induced cellular perturbation?
Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.
Yan
Shi Du
SD
Department of Pathology, College of Physicians & Surgeons of Columbia University, New York City, NY, USA.
Bierhaus
Angelika
A
Nawroth
Peter P
PP
Stern
David M
DM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic