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rdf:type |
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lifeskim:mentions |
umls-concept:C0002395,
umls-concept:C0011155,
umls-concept:C0025936,
umls-concept:C0026336,
umls-concept:C0030685,
umls-concept:C0033640,
umls-concept:C0127400,
umls-concept:C0206116,
umls-concept:C0235032,
umls-concept:C0391871,
umls-concept:C0680255,
umls-concept:C1283071,
umls-concept:C1363844,
umls-concept:C1963578,
umls-concept:C2347946
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pubmed:issue |
33
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pubmed:dateCreated |
2006-8-14
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokines,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/Inflammation Mediators,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/MAP-kinase-activated kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/amyloid beta-protein (1-42),
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
18
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pubmed:volume |
281
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
23658-67
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:16774924-Alzheimer Disease,
pubmed-meshheading:16774924-Amyloid beta-Peptides,
pubmed-meshheading:16774924-Animals,
pubmed-meshheading:16774924-Astrocytes,
pubmed-meshheading:16774924-Cell Line,
pubmed-meshheading:16774924-Cerebral Cortex,
pubmed-meshheading:16774924-Chemokines,
pubmed-meshheading:16774924-Coculture Techniques,
pubmed-meshheading:16774924-Cytokines,
pubmed-meshheading:16774924-Disease Models, Animal,
pubmed-meshheading:16774924-Down-Regulation,
pubmed-meshheading:16774924-Humans,
pubmed-meshheading:16774924-Inflammation Mediators,
pubmed-meshheading:16774924-Interferon-gamma,
pubmed-meshheading:16774924-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:16774924-Lipopolysaccharides,
pubmed-meshheading:16774924-Mice,
pubmed-meshheading:16774924-Mice, Inbred C57BL,
pubmed-meshheading:16774924-Mice, Knockout,
pubmed-meshheading:16774924-Mice, Transgenic,
pubmed-meshheading:16774924-Microglia,
pubmed-meshheading:16774924-Neurons,
pubmed-meshheading:16774924-Peptide Fragments,
pubmed-meshheading:16774924-Phosphorylation,
pubmed-meshheading:16774924-Protein Kinases,
pubmed-meshheading:16774924-Protein-Serine-Threonine Kinases,
pubmed-meshheading:16774924-Rats,
pubmed-meshheading:16774924-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2006
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pubmed:articleTitle |
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.
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pubmed:affiliation |
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
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pubmed:publicationType |
Journal Article
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