Site-Specific Blockade of RAGE-Vd Prevents Amyloid- 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: 6.34). 06/2008; 28(20):5149-58. DOI: 10.1523/JNEUROSCI.4878-07.2008
Source: PubMed


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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    • "When indicated , a polyclonal anti-S100B antibody (DakoCytomation) or polyclonal anti-RAGE antibody (100 nM) was added to the cells at the time point of seeding into wells. The polyclonal anti-RAGE antibody consisted of an equimolar mixture of anti-V, anti-C1 and anti-C2 antibodies as described in our previous publications [34] [35]. 2.7.3. "
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    ABSTRACT: The formation of melanoma metastases from primary tumor cells is a complex phenomenon that involves the regulation of multiple genes. We have previously shown that the receptor for advanced glycation end products (RAGE) was up-regulated in late metastatic stages of melanoma patient samples and we hypothesized that up-regulation of RAGE in cells forming a primary melanoma tumor could contribute to the metastatic switch of these cells. To test our hypothesis, we overexpressed RAGE in the WM115 human melanoma cell line that was established from a primary melanoma tumor of a patient. We show here that overexpression of RAGE in these cells is associated with mesenchymal-like morphologies of the cells. These cells demonstrate higher migration abilities and reduced proliferation properties, suggesting that the cells have switched to a metastatic phenotype. At the molecular level, we show that RAGE overexpression is associated with the up-regulation of the RAGE ligand S100B and the down-regulation of p53, ERK1/2, cyclin E and NF-kB. Our study supports a role of RAGE in the metastatic switch of melanoma cells.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 07/2014; 1842(7). DOI:10.1016/j.bbadis.2014.02.013 · 4.88 Impact Factor
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    • "Also, due to the presence of NF-κB transcriptional elements in its gene promoter [19,20], RAGE activation causes its own sustained over-expression, converting a transient proinflammatory response into a chronic proinflammatory signal [21]. Such positive feedback loop is a potential therapeutic target, and RAGE has been suggested as a biomarker and/or target for intervention in several diseases, including diabetes and its complications [22,23], inflammation [21], tumors [18] and neurodegeneration [2]. Rational design of therapeutic RAGE antagonists or modulators of RAGE activity requires sound structural knowledge of the receptor itself, its structural forms, and its complexes with ligands. "
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    ABSTRACT: Activation of the receptor for advanced glycation end products (RAGE) leads to a chronic proinflammatory signal, affecting patients with a variety of diseases. Potentially beneficial modification of RAGE activity requires understanding the signal transduction mechanism at the molecular level. The ligand binding domain is structurally uncoupled from the cytoplasmic domain, suggesting receptor oligomerization is a requirement for receptor activation. In this study, we used hydrogen-deuterium exchange and mass spectrometry to map structural differences between the monomeric and oligomeric forms of RAGE. Our results indicated the presence of a region shielded from exchange in the oligomeric form of RAGE and led to the identification of a new oligomerization interface localized at the linker region between domains C1 and C2. Based on this finding, a model of a RAGE dimer and higher oligomeric state was constructed.
    PLoS ONE 10/2013; 8(10):e76353. DOI:10.1371/journal.pone.0076353 · 3.23 Impact Factor
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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 · 3.04 Impact Factor
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