Journal
EMBO JOURNAL
Volume 23, Issue 20, Pages 4096-4105Publisher
WILEY
DOI: 10.1038/sj.emboj.7600415
Keywords
neuroinflammation; neuronal degeneration; NF-kappa B activation; synaptic plasticity
Categories
Funding
- NIA NIH HHS [K07 AG000959, AG16223, AG60901, R01 AG018345, AG18345, AG17490, P01 AG017490, 1KO7AG00959] Funding Source: Medline
- CSR NIH HHS [IIRG-00-2076] Funding Source: Medline
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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 Ab-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.
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