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  • The EMBO Journal (2004) 23, 4096 - 4105
  • doi:10.1038/sj.emboj.7600415

Published online: 30 September 2004

RAGE potentiates Abold beta-induced perturbation of neuronal function in transgenic mice

Ottavio Arancio1, Hui Ping Zhang2,a, Xi Chen3, Chang Lin2, Fabrizio Trinchese1, Daniela Puzzo1, Shumin Liu1, Ashok Hegde4, Shi Fang Yan2, Alan Stern2, John S Luddy2, Lih-Fen Lue5, Douglas G Walker5, Alex Roher5, Manuel Buttini6, Lennart Mucke6, Weiying Li7, Ann Marie Schmidt2, Mark Kindy8,9, Paul A Hyslop7, David M Stern10 and Shirley Shi Du Yan2

  1. Department of Psychiatry, Physiology and Neuroscience, Dementia Research Center, Nathan Kline Institute, New York University School of Medicine, NY, USA
  2. Departments of Pathology and Surgery, College of Physicians & Surgeons, Columbia University, NY, USA
  3. Department of Neurology, New York University, NY, USA
  4. Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC, USA
  5. Sun Health Research Institute, Sun City, AZ, USA
  6. Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA, USA
  7. Department of Neurosciences, Eli Lilly & Co., Indianapolis, IN, USA
  8. Department of Physiology and Neuroscience, Neuroscience Institute, Medical University of South Carolina, Charleston, SC, USA
  9. Ralph H. Johnson VA Medical Center, Charleston, SC, USA
  10. School of Medicine, Medical College of Georgia, Augusta, GA, USA

Correspondence to:

Shirley Shi Du Yan, Departments of Pathology and Surgery, Taub Institute for Alzheimer's Disease and the Aging Brain, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA. Tel.: +1 212 305 3958; Fax: +1 12 305 5337; E-mail: sdy1@columbia.edu

aPresent address: Department of Otalaryngology, 1st Affiliated Hospital of Fujian Medical University, Fuzhou, China

Received 10 February 2004; Accepted 25 August 2004

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.

  • Keywords:

    • neuroinflammation,
    • neuronal degeneration,
    • NF-kappaB activation,
    • synaptic plasticity