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IFN-? promotes ? phosphorylation without affecting mature tangles.

ABSTRACT: Inflammatory activation precedes and correlates with accumulating ? lesions in Alzheimer's disease and tauopathies. However, the relationship between neuroinflammation and etiology of pathologic ? 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-?, on ? phosphorylation. In initial studies in primary neuroglial cultures, rAAV-mediated expression of IFN-? did not alter endogenous ? production or paired helical filament ? phosphorylation. Next, we tested the effect of rAAV-mediated expression of IFN-? in the brains of 2 mouse models of tauopathy: JNPL3 and rTg4510. In both models, IFN-? increased 1) signal transducer and activator of transcription 1 levels and gliosis, and 2) hyperphosphorylation and conformational alterations of soluble ? compared with control cohorts. However, sarkosyl-insoluble phosphorylated ? levels and ubiquitin staining were unaltered in the IFN-? cohorts. Notably, IFN-?-induced ? hyperphosphorylation was associated with release of the inhibitory effect of glycogen synthase kinase 3? function by decreasing Ser9 phosphorylation. Our data suggest that type II IFN signaling can promote ? phosphorylation by modulating cellular kinase activity, though this is insufficient in accelerating neuritic tangle pathology.

SUBMITTER: Li A

PROVIDER: S-EPMC6137542 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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IFN-γ promotes τ phosphorylation without affecting mature tangles.

Li Andrew A Ceballos-Diaz Carolina C DiNunno Nadia N Levites Yona Y Cruz Pedro E PE Lewis Jada J Golde Todd E TE Chakrabarty Paramita P

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20150708 10

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 τ phosphorylation. In initial studies in prima ...[more]

PMID: 26156074

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Project description:Alzheimer's Disease (AD) is a devastating neurodegenerative disorder affecting approximately 4 million people in the U.S. alone. AD is characterized by the presence of senile plaques and neurofibrillary tangles in cortical regions of the brain. These pathological markers are thought to be responsible for the massive cortical neurodegeneration and concomitant loss of memory, reasoning, and often aberrant behaviors that are seen in patients with AD. Understanding the molecular mechanisms whereby these histopathological markers develop will greatly enhance our understanding of AD development and progression. A clearer understanding of the mechanisms underlying neurofibrillary tangle formation specifically may help to clarify the basis for dementia of AD as well as the dementias associated with other diseases that are collectively referred to as "tauopathies."; To expression profile both neurons containing neurofibrillary tangles and normal neurons from the entorhinal cortex of 10 mid-stage AD cases. The gene expression profile of neurons that contain neurofibrillary tangles will differ from the expression profile of histopathologically normal neurons from the same patient and from the same brain region. Some of these differences will be informative as to the mechanisms of tangle formation. Experiment Overall Design: First use laser capture microdissection to select 1000 neurons bearing neurofibrillary tangles and 1000 normal neurons from the layer 2 stellate island neurons of the entorhinal cortex of 10 mid-stage AD cases. Second, to isolate the RNA from these captured neurons, perform double round linear amplification and hybridize the labeled cRNA to affymetrix U133A arrays. Third, to use paired, permutational t-tests to analyze the microarray data to select tangle-specific differences in gene expression. For the purposes of submitting this proposal, a value of 1 ug of RNA was entered due to web site constraints on values placed in that field. However, all samples are from LCM captured cells and the actual RNA yield is likely closer to 100 pg.

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IFN-? promotes ? phosphorylation without affecting mature tangles.

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IFN-γ promotes τ phosphorylation without affecting mature tangles.

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