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

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 pro...

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Veröffentlicht in:The FASEB journal 2010-04, Vol.24 (4), p.1043-1055
Hauptverfasser: Fang, Fang, Lue, Lih-Fen, Yan, Shiqiang, Xu, Hongwei, Luddy, John S, Chen, Doris, Walker, Douglas G, Stern, David M, Yan, Shifang, Schmidt, Ann Marie, Chen, John X, Yan, Shirley ShiDu
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Sprache:eng
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Zusammenfassung: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.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.09-139634