IFN-γ promotes τ phosphorylation without affecting mature tangles.

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Neuroinflammation is linked to tau pathology in Alzheimer's disease and tauopathies.
• The precise role of neuroinflammation in the development of pathological tau remains unclear.

Purpose of the Study:

• To investigate if inflammatory signaling, specifically interferon-gamma (IFN-γ), can promote or accelerate the development of neurofibrillary tangle pathology.
• To explore the impact of IFN-γ overexpression on tau phosphorylation and related cellular mechanisms.

Main Methods:

• Recombinant adeno-associated virus (rAAV)-mediated overexpression of IFN-γ in primary neuroglial cultures and in JNPL3 and rTg4510 mouse models of tauopathy.
• Analysis of tau production, phosphorylation, signal transducer and activator of transcription 1 (STAT1) levels, gliosis, and glycogen synthase kinase 3β (GSK3β) activity.

Main Results:

• IFN-γ expression did not alter tau production or paired helical filament tau phosphorylation in primary cultures.
• In mouse models, IFN-γ increased STAT1 levels, gliosis, and hyperphosphorylation of soluble tau.
• IFN-γ did not affect sarkosyl-insoluble phosphorylated tau levels or ubiquitin staining.
• IFN-γ-induced tau hyperphosphorylation was linked to reduced Ser9 phosphorylation of GSK3β, indicating increased kinase activity.

Conclusions:

• Type II IFN signaling can enhance tau phosphorylation by altering cellular kinase activity.
• Despite promoting tau hyperphosphorylation, IFN-γ was insufficient in accelerating neuritic tangle pathology in the studied models.