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

EMBO J. 2004 Oct 13;23(20):4096-105. doi: 10.1038/sj.emboj.7600415. Epub 2004 Sep 30.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Disease Models, Animal
  • Electrophysiology
  • Exploratory Behavior
  • Inflammation / genetics
  • Inflammation / pathology
  • Learning
  • Male
  • Memory
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Neurons / metabolism*
  • Neurons / pathology*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*
  • Synaptophysin / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • NF-kappa B
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Synaptophysin