| Autor: |
Li, Andrew, Ceballos-Diaz, Carolina, DiNunno, Nadia, Levites, Yona, Cruz, Pedro E., Lewis, Jada, Golde, Todd E., Chakrabarty, Paramita |
| Předmět: |
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| Zdroj: |
FASEB Journal; Oct2015, Vol. 29 Issue 10, p4384-4398, 15p |
| Abstrakt: |
Inflammatory activation precedes and correlates with accumulating τ lesions in Alzheimer's disease and tauopathies. However, the relationship between neuroinflammation and etiology of pathologic τ remains elusive. To evaluate whether inflammatory signaling may promote or accelerate neurofibrillary tangle pathology, we explored the effect of recombinant adeno-associated virus (rAAV)-mediated overexpression of a master inflammatory cytokine, IFN-γ, on κ phosphorylation. In initial studies in primary neuroglial cultures, rAAV-mediated expression of IFN-γ did not alter endogenous κ production or paired helical filament κ phosphorylation. Next, we tested the effect of rAAV-mediated expression of IFN-γ in the brains of 2 mouse models of tauopathy: JNPL3 and rTg4510. In both models, IFN-γ increased 1) signal transducer and activator of transcription 1 levels and gliosis, and 2) hyperphosphorylation and conformational alterations of soluble κ compared with control cohorts. However, sarkosyl-insoluble phosphorylated κ levels and ubiquitin staining were unaltered in the IFN-γ cohorts. Notably, IFN-γ-induced κ hyperphosphorylation was associated with release of the inhibitory effect of glycogen synthase kinase 3β function by decreasing Ser9 phosphorylation. Our data suggest that type II IFN signaling can promote κ phosphorylation by modulating cellular kinase activity, though this is insufficient in accelerating neuritic tangle pathology. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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