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.
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 1alpha 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 overexpressed 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 1alpha, 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.
Culbert
Ainsley A
AA
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. ainsley.a.culbert@gsk.com
Skaper
Stephen D
SD
Howlett
David R
DR
Evans
Nicholas A
NA
Facci
Laura
L
Soden
Peter E
PE
Seymour
Zoe M
ZM
Guillot
Florence
F
Gaestel
Matthias
M
Richardson
Jill C
JC
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000201:enzymology* / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D016229:Amyloid beta-Peptides; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C075222:amyloid beta-protein (1-42)