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J. Biol. Chem., Vol. 281, Issue 33, 23658-23667, August 18, 2006

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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^*

Ainsley A. Culbert¹, Stephen D. Skaper, David R. Howlett, Nicholas A. Evans, Laura Facci, Peter E. Soden, Zoe M. Seymour, Florence Guillot, Matthias Gaestel, and Jill C. Richardson

From the Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, Essex, United Kingdom and the Medical School Hannover, Institute of Biochemistry, 30625 Hannover, Germany

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 -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 , KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1 on stimulation with LPS + interferon or amyloid- 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 -stimulated or amyloid- 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 overexpressed in specific regions of the brain, elevated activation and expression of MK2 correlated with -amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor , macrophage inflammatory protein 1, 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.

Received for publication, December 22, 2005 , and in revised form, June 12, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-1279-622649; Fax: 44-1279-6222555; E-mail: ainsley.a.culbert{at}gsk.com.

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