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

ABSTRACT:

Introduction

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.

Methods

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).

Results

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.

Discussion

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.

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.

SUBMITTER: Sanford SAI 

PROVIDER: S-EPMC10916982 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature