Article

Site-specific blockade of RAGE-Vd prevents amyloid-β oligomer neurotoxicity

Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zurich, 8032 Zurich, Switzerland.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 06/2008; 28(20):5149-58. DOI: 10.1523/JNEUROSCI.4878-07.2008
Source: PubMed

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.

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    • "While RAGE was identified as potential binding receptor for oligomeric Aβ species prior to the other protein receptors, its discovery as mediator of oAβ was obtained using high concentrations (10 μM) of synthetic Aβ 1–40 (Sturchler et al. 2008). Using 10 μM mixtures of oAβ with unknown stoichiometry or relative abundance, RAGE was found to bind oAβ when compared to A11-immunonegative Aβ fibrils or aggregates (Sturchler et al. 2008). It is unfortunate that monomeric Aβ preparations were not tested in parallel to synthetic oAβ. "
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    • "Among them are the P75 neurotrophin receptors, the antibody-based blockade of which prevents cell death after exposure to relatively high doses of Aβ oligomers (Knowles et al. 2009); the receptor for advanced glycation endproducts, or " RAGE " (Sturchler et al. 2008); the frizzled receptor (Magdesian et al. 2008), and nicotinic acetylcholine receptors (Magdesian et al. 2005), which were shown to bind monomeric Aβ peptides. "
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