Signatures 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.
We 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).
Polyinosinic: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.
We 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.
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.
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This post is Copyright: Sophie A. I. Sanford,
Lauren V. C. Miller,
Benjamin J. Tuck,
Leo C. James,
William A. McEwan | October 18, 2023