biostudies-literatureSanford SAIUK Dementia Research InstituteMedical Research CouncilAlzheimer's SocietyWellcome Trust1013-1025https://www.ebi.ac.uk/biostudies/studies/S-EPMC10916982biostudies-literatureUnknown20(2)<h4>Introduction</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Discussion</h4>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.<h4>Highlights</h4>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.Alzheimer's & dementia : the journal of the Alzheimer's AssociationThe type-I interferon response potentiates seeded tau aggregation and exacerbates tau pathology.PMC10916982MC_U105181010UKDRI-2010488206248/Z/17/Z223054/Z/21/ZSanford SAISyanda VVaysburd MClark JJames LCMcEwan WATuck BJMiller LVCKeeling SNeumann MfalseThe type-I interferon response potentiates seeded tau aggregation and exacerbates tau pathology.<h4>Introduction</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Discussion</h4>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.<h4>Highlights</h4>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.2024-01-01T00:00:00Z2024 Feb2025-04-20T02:52:09.072Z2025-04-20T02:52:09.072ZS-EPMC109169823784902610.1002/alz.13493