The receptor for advanced glycosylation end products (RAGE) has been implicated in mediating beta amyloid (A(3) toxicity and contributing to Alzheimer's disease (AD) pathogenesis, although the specifics on many aspects of RAGE biology and toxicity remain to be elucidated. Recent reports have demonstrated that, in contrast to the transmembrane RAGE receptor, the secreted or soluble forms of RAGE (sRAGE) are capable of suppressing several aspects of Ap pathogenesis in vivo. Pilot studies from our laboratory demonstrate 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 these observations. The goal of this proposal is to test two related hypotheses. The first hypothesis is that increases in RAGE-ligand interactions occur during the progression of AD and in a transgenic mouse model of Ap pathogenesis, with oligomeric Ap representing a significant portion of the overall RAGE-ligand interactions. The second hypothesis is that sRAGE inhibits the formation of pathogenic p 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-ligand interactions in AD and APP/PS-1 mice, 2) To elucidate the functional domains responsible for RAGE- Ap interactions, 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 to eventual treatments for AD. Additionally, these findings will be critical in clarifying the current gaps that exist in our understanding of RAGE with Ap-assembly, Ap-deposition, and Ap-induced neurotoxicity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of Kentucky
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