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

Fang, Lih Fen Lue, Shiqiang Yan, Hongwei Xu, John S. Luddy, Doris Chen, Douglas G. Walker, David Stern, Shifang Yan, Ann Marie Schmidt, John X. Chen, Shirley Shi Du Yan

Research output: Contribution to journalArticle

163 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1043-1055
Number of pages13
JournalFASEB Journal
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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Microglia
Alzheimer Disease
Learning
Data storage equipment
Amyloid
Deterioration
Signal transduction
Esterases
Interleukin-1
Infiltration
Astrocytes
Transgenic Mice
Acetylcholine
Neurons
Signal Transduction
Advanced Glycosylation End Product-Specific Receptor

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. / Fang; Lue, Lih Fen; Yan, Shiqiang; Xu, Hongwei; Luddy, John S.; Chen, Doris; Walker, Douglas G.; Stern, David; Yan, Shifang; Schmidt, Ann Marie; Chen, John X.; Yan, Shirley Shi Du.

In: FASEB Journal, Vol. 24, No. 4, 01.04.2010, p. 1043-1055.

Research output: Contribution to journalArticle

Fang, Lue, LF, Yan, S, Xu, H, Luddy, JS, Chen, D, Walker, DG, Stern, D, Yan, S, Schmidt, AM, Chen, JX & Yan, SSD 2010, 'RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease', FASEB Journal, vol. 24, no. 4, pp. 1043-1055. https://doi.org/10.1096/fj.09-139634
Fang ; Lue, Lih Fen ; Yan, Shiqiang ; Xu, Hongwei ; Luddy, John S. ; Chen, Doris ; Walker, Douglas G. ; Stern, David ; Yan, Shifang ; Schmidt, Ann Marie ; Chen, John X. ; Yan, Shirley Shi Du. / RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. In: FASEB Journal. 2010 ; Vol. 24, No. 4. pp. 1043-1055.
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