biostudies-literatureUnknownNaguib SNIA NIH HHSThe Christchurch mutation (R136S) on the APOE3 (E3 S/S ) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the specific molecular mechanisms enabling the E3 S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse ApoE with wild-type human E3 or E3 S/S on a tauopathy background. The R136S mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the R136S mutation reduced interferon response to tau bioRxiv : the preprint server for biology2024.04.25.591140https://www.ebi.ac.uk/biostudies/studies/S-EPMC11071490biostudies-literatureAPOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.PMC11071490R01 AG072758F32 AG085960RF1 AG079557R01 AG074541R01 AG079291Lopez-Lee CNorinsky RGong STorres ERNorman KWu ZZhao MBhagwat MPatel TMok SAFan LWang WWong MYAmbaw YALee SICastaneda RZhu DFarese RVNaguib SZhu JSinha SYe PGan LLuo WWalther TCfalseAPOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.The Christchurch mutation (R136S) on the APOE3 (E3 S/S ) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the specific molecular mechanisms enabling the E3 S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse ApoE with wild-type human E3 or E3 S/S on a tauopathy background. The R136S mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the R136S mutation reduced interferon response to tau 2025-01-01T00:00:00Z2025 Jan2026-05-30T03:11:36.532Z2026-05-30T03:06:40.819ZS-EPMC110714903871216410.1101/2024.04.25.591140