title: Inhibition of JAK2 attenuates the increase in inflammatory markers in microglia from APP/PS1 mice.
abstract: There is a wealth of evidence indicating that macrophages adopt distinct phenotypes when exposed to specific stimuli and, in the past few years, accumulating data suggest that microglia behave somewhat similarly. Therefore, microglia can adopt the so-called M1 or M2 phenotypes in response to interferon-γ (IFNγ) and interleukin-4, respectively. Although it has yet to be unequivocally proven in the context of microglia, acutely activated M1 cells are probably protective, although a persistent M1 state is likely to be damaging, whereas M2 cells may be reparative and restorative. In this case, particularly because the current evidence suggests the development of a predominantly M1 state with age and in neurodegenerative diseases, it is important to identify mechanisms by which polarization of microglia can be modulated. The present findings indicate that exposure of cultured microglia to IFNγ increased expressions of the archetypal markers of the M1 phenotype, tumour necrosis factor-α, and inducible nitric oxide synthase, and preexposure of cells to amyloid-β (Aβ) sensitized microglia to subsequent stimulation with IFNγ. Importantly, this synergy was also evident in microglia prepared from the brains of transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1, APP/PS1 mice) and are exposed to a combination of increasing concentrations of endogenous Aβ from 4 or 5 months of age and an age-related increase in IFNγ. Significantly, the JAK2 inhibitor, TG101209, attenuated the IFNγ-induced changes in cultured microglia and in isolated microglia prepared from APP/PS1 mice. These findings suggest that targeting JAK2 may be a potential strategy for reducing neuroinflammation in Alzheimer's disease.
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
authors.forename: Raasay S
authors.initials: RS
authors.lastname: Jones
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
authors.forename: Aedín M
authors.initials: AM
authors.lastname: Minogue
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Fitzpatrick
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland. Electronic address: lynchma@tcd.ie.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology; D016229:Amyloid beta-Peptides; D000818:Animals; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D052247:Nitric Oxide Synthase Type II; D053764:Presenilin-1; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha; D000096926:Benzenesulfonamides
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D007371:Interferon-gamma; D053614:Janus Kinase 2; D052247:Nitric Oxide Synthase Type II; D053764:Presenilin-1; D011743:Pyrimidines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C522865:TG101209; D000096926:Benzenesulfonamides; C507926:Jak2 protein, mouse
keywords: APP/PS1; JAK2; M1/M2; Microglia; TG101209