Cited by 336Neuroinflammation and Neurodegeneration MechanismsAdvanced Glycation End Products researchAlzheimer's disease research and treatments

RAGE‐dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease

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Fang, Fang, Lue, Lih-Fen, Yan, Shiqiang, Xu, Hongwei, Luddy, John S., Chen, Doris, Walker, Douglas G., Stern, David M. +4 more·2010·The FASEB Journal

Abstract

Microglia are critical for amyloid‐β peptide (Aβ)‐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, Aβ accumulation, impaired learning/memory, and neurotoxicity in an Aβ‐rich environment. Transgenic (Tg) mice expressing human mutant APP (mAPP) in neurons and RAGE in microglia displayed enhanced IL‐1β and TNF‐α production, increased infiltration of microglia and astrocytes, accumulation of Aβ, 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 Aβ. 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 Aβ‐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, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 24, 1043–1055 (2010). www.fasebj.org

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  • In APP transgenic mice, overexpression of RAGE in microglia increases glial infiltration and Aβ accumulation, and exacerbates cognitive impairment.

    “In APP transgenic mice, overexpression of RAGE in microglia increases glial infiltration and Aβ accumulation, and exacerbates cognitive function [375].”
  • RAGE expression by microglial cells contributed to neuroinflammation in a mouse model of Alzheimer's disease.

    “In addition, the binding of β-amyloid to RAGe results in activated microglial cells94, and RAGe expression by microglial cells contributed to neuroinflammation in a mouse model of Alzheimer's disease89.”

    From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [89]

  • RAGE is a transmembrane receptor expressed by immune cells, endothelial cells, cardiomyocytes and neurons.

    “RAGe is a transmembrane receptor that is expressed by immune cells, endothelial cells, cardiomyocytes and neurons89–91.”

    From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [89]

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Authors
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.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Banner Sun Health Research Institute (US)
  • Harbin Medical University (CN)
  • University of Cincinnati (US)
  • Department of Surgery College of Physicians and Surgeons Columbia University New York New York USA
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Yan, Shirley ShiDu
Venue
The FASEB Journal
Publisher
Wiley
Published
2009-11-11
Volume
24
Issue
4
Pages
1043-1055
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
OpenAlex
W2054082659
Cited by
335
References
81
Citations by year
2026: 20 · 2025: 23 · 2024: 14 · 2023: 16 · 2022: 23 · 2021: 32 · 2020: 21 · 2019: 18 · 2018: 7 · 2017: 16 · 2016: 23 · 2015: 25 · 2014: 30 · 2013: 19 · 2012: 24
FWCI
10.25
Type
journal article
Language
en
Open access
Locations
  • The FASEB Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service (PO1AG17490)
  • Arizona Alzheimer’s Consortium
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
receptor for advanced glycation end products, RAGE signaling, microglia, neuroinflammation, amyloid-beta deposition, Alzheimer's disease, learning and memory impairment, IL-1β, TNF-α, acetylcholinesterase activity, APP transgenic mice, neurotoxicity
MeSH terms
Receptor for Advanced Glycation End Products, Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Humans, Inflammation, Learning, Memory, Mice, Transgenic, Mutation, Neurons, Tumor Necrosis Factor-alpha, Signal Transduction, Amyloid beta-Peptides, Microglia, Mitogen-Activated Protein Kinases, Mice, Interleukin-1beta

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