Document Detail

RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease.
MedLine Citation:
PMID:  19906677     Owner:  NLM     Status:  MEDLINE    
Microglia are critical for amyloid-beta peptide (Abeta)-mediated neuronal perturbation relevant to Alzheimer's disease (AD) pathogenesis. We demonstrate that overexpression of receptor for advanced glycation end products (RAGE) in imbroglio exaggerates neuroinflammation, as evidenced by increased proinflammatory mediator production, Abeta accumulation, impaired learning/memory, and neurotoxicity in an Abeta-rich environment. Transgenic (Tg) mice expressing human mutant APP (mAPP) in neurons and RAGE in microglia displayed enhanced IL-1beta and TNF-alpha production, increased infiltration of microglia and astrocytes, accumulation of Abeta, reduced acetylcholine esterase (AChE) activity, and accelerated deterioration of spatial learning/memory. Notably, introduction of a signal transduction-defective mutant RAGE (DN-RAGE) to microglia attenuates deterioration induced by Abeta. These findings indicate that RAGE signaling in microglia contributes to the pathogenesis of an inflammatory response that ultimately impairs neuronal function and directly affects amyloid accumulation. We conclude that blockade of microglial RAGE may have a beneficial effect on Abeta-mediated neuronal perturbation relevant to AD pathogenesis.-Fang, F., Lue, L.-F., Yan, S., Xu, H., Luddy, J. S., Chen, D., Walker, D. G., Stern, D. M., Yan, S., Schmidt, A. M., Chen, J. X., Yan, S. S. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease.
Fang Fang; Lih-Fen Lue; Shiqiang Yan; Hongwei Xu; John S Luddy; Doris Chen; Douglas G Walker; David M Stern; Shifang Yan; Ann Marie Schmidt; John X Chen; Shirley ShiDu Yan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2009-11-11
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  24     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-01     Completed Date:  2010-04-28     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1043-55     Citation Subset:  IM    
P&S 17-410, Department Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th St., New York, NY 10032, USA.
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MeSH Terms
Alzheimer Disease / genetics,  metabolism*,  pathology
Amyloid beta-Peptides / genetics,  metabolism*
Antigens, Neoplasm
Astrocytes / metabolism,  pathology
Disease Models, Animal
Inflammation / genetics,  metabolism,  pathology
Interleukin-1beta / genetics,  metabolism
Mice, Transgenic
Microglia / metabolism*,  pathology
Mitogen-Activated Protein Kinases / genetics,  metabolism*
Neurons / metabolism,  pathology
Signal Transduction*
Tumor Necrosis Factor-alpha / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Antigens, Neoplasm; 0/Interleukin-1beta; 0/Tumor Necrosis Factor-alpha; EC 2.7.1.-/Stk30 protein, mouse; EC protein, human; EC Protein Kinases

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