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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    • "A␤ is also a ligand for RAGE on neurons and microglial cells (Verdier et al., 2004). The V and C1 domains of RAGE bind to A␤ oligomers and aggregates, respectively, and blocking these two forms prevented A␤-induced neurotoxicity (Sturchler et al., 2008). "
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    ABSTRACT: Pattern-recognition receptors have been highly conserved in evolution. They recognize danger signals including both pathogen- and damage-associated molecular patterns, also known as alarmins. Several signaling pathways leading to an inflammatory reaction as part of an effective defensive response, are thus triggered. RAGE, a receptor initially considered for advanced glycation end-products, is also known to be activated by several danger signals, thus functioning as a pattern-recognition receptor. As a new member of this family, attempts to unraveling its functioning show that RAGE activation not only results in innate immune response but also contributes to promote and shape the acquired immune reaction. As reported for other members of the family, RAGE presents many polymorphic variants and additional studies are needed to elucidate its significance in immune response and disease susceptibility. Here we describe recent advances unraveling RAGE functions, as well as its significance and challenges in immunobiology.
    Immunobiology 10/2012; 218(5). DOI:10.1016/j.imbio.2012.09.005
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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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    ABSTRACT: For nearly 100 years following the first description of this neurological disorder by Dr Alois Alzheimer, amyloid plaques and neurofibrillary tangles have been hypothesized to cause neuronal loss. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to induce the deleterious cascade(s) involved in the pathophysiology of Alzheimer's disease. In this review, we will discuss our current understanding about endogenous oligomeric Aβ production, their relative toxicity in vivo and in vitro, and explore the potential future directions needed for the field.
    Journal of Neurochemistry 11/2011; 120 Suppl 1(Suppl 1):125-39. DOI:10.1111/j.1471-4159.2011.07478.x
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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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    ABSTRACT: Aβ oligomers cause a collection of molecular events associated with memory loss in Alzheimer's disease, centering on disrupting the maintenance of synapse structure and function. In this brief review of the synaptotoxic effects of Aβ oligomers, we focus on the neuronal properties governing oligomer targeting and toxicity-especially with respect to binding sites and mechanisms of binding. We also discuss ways in which mechanistic insights from other diseases offer clues in the pursuit of the molecular basis of Alzheimer's disease.
    Cellular and Molecular Neurobiology 05/2011; 31(6):939-48. DOI:10.1007/s10571-011-9691-4
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