The type‐I interferon response potentiates seeded tau aggregation and exacerbates tau pathology

Abstract

INTRODUCTIONSignatures of a type‐I interferon (IFN‐I) response are observed in the post mortem brain in Alzheimer's disease (AD) and other tauopathies. However, the effect of the IFN‐I response on pathological tau accumulation remains unclear.METHODSWe examined the effects of IFN‐I signaling in primary neural culture models of seeded tau aggregation and P301S‐tau transgenic mouse models in the context of genetic deletion of the IFN‐I receptor (IFNAR).RESULTSPolyinosinic:polycytidylic acid (PolyI:C), a synthetic analog of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau in an IFN‐I‐dependent manner. IFN‐I‐induced vulnerability could be pharmacologically prevented and was intrinsic to neurons. Aged P301S‐tau mice lacking Ifnar1 had significantly reduced tau pathology compared to mice with intact IFN signaling.DISCUSSIONWe identify a critical role for IFN‐I in potentiating tau aggregation. IFN‐I is therefore identified as a potential therapeutic target in AD and other tauopathies.Highlights Type‐I IFN (IFN‐I) promotes seeded tau aggregation in neural cultures. IFNAR inhibition prevents IFN‐I driven sensitivity to tau aggregation. IFN‐I driven vulnerability is intrinsic to neurons. Tau pathology is significantly reduced in aged P301S‐tau mice lacking IFNAR.

Amyloid precursor protein induces reactive astrogliosis

“…It is therefore plausible to hypothesize that such a feedback loop plays a role in IFN‐induced remodeling of the intermediate filament network in the reactive astrocytes 94–99 . Emerging data showing that APP binds to and modifies regulators of cytokine expression, 100–103 together with reportedly blunted innate immune response observed in mice deficient in APP, 104 also suggest that consequences of the interplay between APP and the immune networks might be significantly more far‐reaching than previously thought 105 …”

“…[94][95][96][97][98][99] Emerging data showing that APP binds to and modifies regulators of cytokine expression, [100][101][102][103] together with reportedly blunted innate immune response observed in mice deficient in APP, 104 also suggest that consequences of the interplay between APP and the immune networks might be significantly more far-reaching than previously thought. 105…”

Amyloid precursor protein induces reactive astrogliosis

“…It is plausible to hypothesize that such a positive feedback loop plays a role in IFN-induced remodelling of the intermediate filament network in the reactive astrocytes 93–98 . Emerging data showing that APP binds to and modifies regulators of cytokine expression 99–102 , together with reportedly blunted innate immune response observed in mice deficient in APP 103 , also suggest that consequences of the interplay between APP and the immune networks might be significantly more far-reaching than previously thought 104 .…”

In sickness and in health—Type I interferon and the brain

“…Remarkably, an IFN-I signature is prevalent in both human AD and mouse brains developing tauopathy ( Rexach et al, 2020 ; Roy et al, 2020 ). Interestingly, exogenous IFN-I treatment significantly potentiates seeded tau aggregation in mixed neural cultures in vitro ( Sanford et al, 2024 ). Moreover, the brains of aged P301S-tau mice lacking Ifnar1 contain markedly reduced tau pathology, indicating a pathogenic involvement of IFN-I.…”