The type‐I interferon response potentiates seeded tau aggregation and exacerbates tau pathology
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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.
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Type I interferon signaling exacerbates tau seeding.
“Previous studies have shown that type I interferon signaling was found to exacerbate tau seeding46.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [46]
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Cited by
Sorted by citations
Naguib, S., Lopez-Lee, C., Torres, E. R., Lee, S.-I., Zhu, J., Zhu, D., Ye, P., Norman, K., Zhao, M., Wong, M. Y., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.05.023 · Cited by 32 · see citing works
- Authors
- Sanford, S. A. I., Miller, L. V. C., Vaysburd, M., Keeling, S., Tuck, B. J., Clark, J., Neumann, M., Syanda, V., James, L. C., & McEwan, W. A.
- Affiliations
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Sanford, Sophie A. I.
- McEwan, William A.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2023-10-17
- Volume
- 20
- Issue
- 2
- Pages
- 1013-1025
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC10916982
- OpenAlex
- W4387728549
- Cited by
- 26
- References
- 9
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 12 · 2023: 1
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- UK Dementia Research Institute
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- type I interferon, tau aggregation
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Interferon Type I, Mice, Transgenic, tau Proteins, Tauopathies, Mice
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