MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity - Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease

被引:135
作者
Culbert, Ainsley A.
Skaper, Stephen D.
Howlett, David R.
Evans, Nicholas A.
Facci, Laura
Soden, Peter E.
Seymour, Zoe M.
Guillot, Florence
Gaestel, Matthias
Richardson, Jill C.
机构
[1] GlaxoSmithKline Res & Dev Ltd, Neurol & GI Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England
[2] Hannover Med Sch, Inst Biochem, D-30625 Hannover, Germany
关键词
D O I
10.1074/jbc.M513646200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MAPK-activated protein kinase 2 (MAPKAP K2 or MK2) is one of several kinases directly regulated by p38 MAPK. A role for p38 MAPK in the pathology of Alzheimer disease (AD) has previously been suggested. Here, we provide evidence to suggest that MK2 also plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon gamma-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response. Microglia cultured ex vivo from MK2-deficient (MK2(-/-)) mice demonstrated significant inhibition in release of tumor necrosis factor alpha, KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1 alpha on stimulation with LPS + interferon gamma or amyloid-beta peptide (1-42) compared with MK2(+/+) wild-type microglia. Consistent with an inhibition in pro- inflammatory mediator release, cortical neurons co-cultured with LPS + interferon gamma-stimulated or amyloid-beta peptide (1-42) stimulated MK2(+/+) microglia were protected from microglial-mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein and presenilin-1 harboring familial AD mutations are over-expressed in specific regions of the brain, elevated activation and expression of MK2 correlated with beta-amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, and KC gene expression in the same brain regions. Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented.
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页码:23658 / 23667
页数:10
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