Type‐I interferon promotes tau pathology by potentiating seeded aggregation

Abstract

AbstractBackgroundRecent work has implicated antiviral type‐I interferon (IFN) cytokines in Alzheimer’s disease (AD) and related tauopathies. Signatures of type‐I IFN‐driven gene expression are observed in the post‐mortem AD brain. Whilst the effects of type‐I IFN on β‐amyloid pathology have been previously investigated, its effects on tau pathology remain unclear.MethodWe examined the effects of type‐I IFN signalling on tau pathology ex vivo using primary neural culture models of seeded tau aggregation. In vivo, P301S‐tau transgenic mice were bred as homozygous knockout for the type‐I IFN receptor, Ifnar. Ifnar‐/‐ animals were compared with Ifnar+/+ for the extent of tau pathology by immunostaining.ResultTreatment of neural cultures with polyI:C, a synthetic analogue of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau. Type‐I IFN was the principal driver of this response, as Ifnar‐/‐ cultures were protected from the pro‐aggregant effects of polyI:C or exogenous type‐I IFN treatment. Pharmacological antagonists of IFN signalling prevented the effects of type‐I IFN. These effects of type‐I IFN were independent of microglia, as the phenotype remained when Iba1+ cells were pharmacologically depleted. Tau pathology was significantly reduced in aged Ifnar‐/‐ P301S‐tau mice relative to Ifnar+/+ P301S‐tau mice, consistent with IFN signalling driving tau pathology.ConclusionOur data shows a novel role for type‐I IFNs in the development of tau pathology both in vivo and ex vivo. This implicates the type‐I IFN response as a potential target for therapeutic intervention in AD and tauopathies.