Site-Specific Blockade of RAGE-V_dPrevents Amyloid-β Oligomer Neurotoxicity

Abstract

In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-␤ peptide (A␤) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that A␤ had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric A␤ species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of A␤ 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 A␤. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized A␤ conformations: A␤ oligomers (A␤Os), A␤ fibrils (A␤Fs), and A␤ aggregates (A␤As). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either A␤Os or A␤As but does not affect A␤F toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V d domain of RAGE attenuates A␤O-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of A␤A-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 A␤-induced cellular and neuronal toxicity with respect to the A␤ aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

“…The major features of RAGE activation in contributing to AD result from its interaction with A␤. RAGE interaction with A␤ results in perturbation of neuronal function, amplification of glial inflammatory response, elevation of oxidative stress and amyloidosis, and increased A␤ influx at the BBB (75)(76)(77)(78). Our results suggest that A␤-RAGE interaction at the BBB links the intracerebral A␤ deposition to systemic immune T cells by up-regulating CCR5 on brain endothelial cells.…”

RAGE: The Beneficial and Deleterious Effects by Diverse Mechanisms of Actions

“…Notably, the amounts of Aβ deposits and plaques increase by overexpression of fulllength RAGE, not by sRAGE (Cho et al, 2009). RAGE binds to diverse forms of Aβ: Aβ oligomer and aggregate and nonfibrillar and fibrillar forms of Aβ (Sturchler et al, 2008;Verdier et al, 2004). Kinetic studies suggest that purified RAGE binds specifically to Aβ (K d = 57 ± 14 nM), similar to K d values in endothelial and cortical neurons (40 ± 10 nM and 55 ± 15 nM, respectively) .…”

“…In addition, different binding sites can exist for aggregated ligands. RAGE is implicated in Aβ oligomer-and Aβ aggregate-induced apoptosis in SH-SY5Y cells (not Aβ fibrils), and distinct regions of RAGE mediate the binding of various conformations of Aβ; the V d domain is important for Aβ oligomer binding to RAGE, and the C 1d domain controls the ligation of Aβ aggregates (Sturchler et al, 2008).…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Many of these molecules are critical elements responsible for shaping and maintaining anatomical structures on neurons and mediating signaling pathways that control neuronal communication. In recent years, numerous studies have identified several putative receptors for Aβ oligomers, including α7-nAChR (7), RAGE (8), PrP c (9), mGluR5 (10,11), insulin receptor (12), EphB2 receptor (13,14), human LilrB2 (15), the p75 neurotrophic receptor (16) and reelin (17). Interaction of Aβ oligomers with these receptors might constitute crucial events leading to morphological and functional changes of dendritic spines associated with cognitive impairment in AD (4,18).…”