The receptor for advanced glycosylation end products (RAGE) has been implicated in mediating betaamyloid (A(3) toxicity and contributing to Alzheimer's disease (AD) pathogenesis, although the specifics onmany aspects of RAGE biology and toxicity remain to be elucidated. Recent reports have demonstratedthat, in contrast to the transmembrane RAGE receptor, the secreted or soluble forms of RAGE (sRAGE) arecapable of suppressing several aspects of Ap pathogenesis in vivo. Pilot studies from our laboratorydemonstrate that sRAGE suppresses the formation of assembled A(3 species and Ap -induced neurotoxicity,with sRAGE interacting with the oligomeric forms of Ap at higher apparent affinity than monomeric Ap.However, it is currently not known which regions of sRAGE are responsible for mediating each of theseobservations. The goal of this proposal is to test two related hypotheses. The first hypothesis is thatincreases in RAGE-ligand interactions occur during the progression of AD and in a transgenicmouse model of Ap pathogenesis, with oligomeric Ap representing a significant portion of the overallRAGE-ligand interactions. The second hypothesis is that sRAGE inhibits the formation of pathogenicp and the effects of pathogenic Ap, via specific and related domains within the sRAGE protein.
The specific aims to test each of these hypotheses are as follows: 1) To define the alterations in RAGE-ligandinteractions in AD and APP/PS-1 mice, 2) To elucidate the functional domains responsible for RAGE- Apinteractions, 3) To determine the mechanism by which sRAGE suppresses Ap-induced neurotoxicity, and 4)To determine the mechanism by which sRAGE suppresses Ap assembly and Ap deposition. Cumulatively,these data will advance the field by potentially identifying novel therapeutic strategies that could lead toeventual treatments for AD. Additionally, these findings will be critical in clarifying the current gaps that existin our understanding of RAGE with Ap-assembly, Ap-deposition, and Ap-induced neurotoxicity.
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