<i>APOE3</i>-<i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.

ABSTRACT: 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

SUBMITTER: Naguib S 

PROVIDER: S-EPMC11071490 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature