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RAGE potentiates Aβ‐induced perturbation of neuronal function in transgenic mice
Author(s) -
Arancio Ottavio,
Zhang Hui Ping,
Chen Xi,
Lin Chang,
Trinchese Fabrizio,
Puzzo Daniela,
Liu Shumin,
Hegde Ashok,
Yan Shi Fang,
Stern Alan,
Luddy John S,
Lue LihFen,
Walker Douglas G,
Roher Alex,
Buttini Manuel,
Mucke Lennart,
Li Weiying,
Schmidt Ann Marie,
Kindy Mark,
Hyslop Paul A,
Stern David M,
Du Yan Shirley Shi
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600415
Subject(s) - rage (emotion) , biology , neuroscience , receptor , genetically modified mouse , transgene , amyloid precursor protein , immunoglobulin superfamily , glycation , alzheimer's disease , microbiology and biotechnology , medicine , biochemistry , disease , gene
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 (Aβ). 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 Aβ‐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 Aβ‐induced neuronal perturbation in a model of Alzheimer's‐type pathology, and suggest its potential as a therapeutic target to ameliorate cellular dysfunction.