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EMBO J. 2004 Oct 13;23(20):4096-105. Epub 2004 Sep 30.

RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice.

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  • 1Department of Psychiatry, Physiology and Neuroscience, Dementia Research Center, Nathan Kline Institute, New York University School of Medicine, NY 10032, USA.

Abstract

Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta). In view of increased neuronal expression of RAGE in Alzheimer's disease, a murine model was developed to assess the impact of RAGE in an Abeta-rich environment, employing transgenics (Tgs) with targeted neuronal overexpression of RAGE and mutant amyloid precursor protein (APP). Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice. In contrast, Tg mice bearing a dominant-negative RAGE construct targeted to neurons crossed with mAPP animals displayed preservation of spatial learning/memory and diminished neuropathologic changes. These data indicate that RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology, and suggest its potential as a therapeutic target to ameliorate cellular dysfunction.

PMID:
15457210
[PubMed - indexed for MEDLINE]
PMCID:
PMC524347
Free PMC Article

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