P3–276: MAPKAP kinase 2 deficiency in microglia inhibits pro–inflammatory mediator release and resultant neurotoxicity: Relevance to neuroinflammation in a transgenic mouse model of Alzheimer's disease

A role for p38 mitogen–activated protein (MAP) kinase in the pathology of Alzheimer's disease (AD) has previously been suggested. MAP kinase–activated protein kinase 2 (MAPKAP kinase 2 or MK2) is one of several kinases directly regulated by p38 MAP kinase. We sought to investigate whether MK2 itself plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. We investigated the role of MK2 in isolated microglial cell cultures, in co–cultures of cortical neurons and microglia, and in the CNS tissue of a transgenic mouse model of AD. MK2 expression was enriched in primary cultures of cortical microglial cells compared to other CNS cell types, favouring a function for MK2 in the former. Furthermore, MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon–γ (IFNγ)–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 tumour necrosis factor alpha (TNF–α), KC and macrophage inflammatory protein 1 alpha (MIP–1α) on stimulation with LPS+IFNγ or amyloid–β peptide (1–42) compared to MK2+/+ microglia. Consistent with an inhibition in pro–inflammatory mediator release, cortical neurons co–cultured with LPS+IFNγ–stimulated MK2–/– microglia were protected from microglial–mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein (APP) and presenilin–1 (PS–1) harbouring familial AD mutations are over–expressed in specific regions of the brain, elevated activation and expression of MK2 correlated with β–amyloid deposition, microglial activation and upregulation of TNF–α, MIP–1α 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.