Affiliations: [a] Department of Pathology, College of Physicians & Surgeons of Columbia University, New York City, NY, USA | [b] Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany | [c] Dean/VPHA Office, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
Correspondence:
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Corresponding author: David M. Stern, MD, Dean/VPHA Office, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, PO Box 670555, Cincinnati, OH 45267-0555, USA. Tel.: +1 513 558 7334; Fax: +1 513 558 3512; E-mail: david.stern@uc.edu.
Abstract: 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-β peptide (Aβ) 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 Aβ-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 Aβ-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Aβ-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-β protein precursor. Interception of Aβ interaction with RAGE, by infusion of soluble RAGE, decreases Aβ content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Aβ accumulation. These data suggest that RAGE may be a therapeutic target for AD.
