title: Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity.
abstract: In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-beta peptide (Abeta) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that Abeta had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric Abeta species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. The receptor for advanced glycation end products (RAGE), a member of the Ig superfamily, is a cellular binding site for Abeta. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized Abeta conformations: Abeta oligomers (AbetaOs), Abeta fibrils (AbetaFs), and Abeta aggregates (AbetaAs). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either AbetaOs or AbetaAs but does not affect AbetaF toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V(d) domain of RAGE attenuates AbetaO-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of AbetaA-induced apoptosis requires the neutralization of the C(1d) domain of the receptor. Thus, our data indicate that distinct regions of RAGE are involved in Abeta-induced cellular and neuronal toxicity with respect to the Abeta aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.
authors.affiliation: Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zurich, 8032 Zurich, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sturchler
authors.forename: Arnaud
authors.initials: A
authors.lastname: Galichet
authors.forename: Mirjam
authors.initials: M
authors.lastname: Weibel
authors.forename: Estelle
authors.initials: E
authors.lastname: Leclerc
authors.forename: Claus W
authors.initials: CW
authors.lastname: Heizmann
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000918:Antibody Specificity / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D009498:Neurotoxins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic