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

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...

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Bibliographic Details
Published in:Alzheimer's & dementia 2024-02, Vol.20 (2), p.1013-1025
Main Authors: Sanford, Sophie A. I., Miller, Lauren V. C., Vaysburd, Marina, Keeling, Sophie, Tuck, Benjamin J., Clark, Jessica, Neumann, Michal, Syanda, Victoria, James, Leo C., McEwan, William A.
Format: Article
Language:English
Subjects:
Accumulation
Acids
Alzheimer's disease
Animals
Brain research
Cytokines
Deoxyribonucleic acid
DNA
Heparan sulfate
innate immunity
Interferon
Kinases
Neurodegeneration
neuroinflammation
Neurons
Pathogens
Pathology
Signaling
tau pathology
tauopathy
Transgenic animals
Vulnerability
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Summary: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.
ISSN:1552-5260
1552-5279
1552-5279
DOI:10.1002/alz.13493