APOE3 - R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.
Overview
abstract
UNLABELLED: The Christchurch mutation (R136S) on the APOE3 ( E3 S/S ) gene is associated with low tau pathology and slowdown of cognitive decline despite the causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier 1 . However, the molecular effects enabling E3 S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3 S/S on a tauopathy background. The R136S mutation markedly mitigated tau load and protected against tau-induced synaptic loss, myelin loss, and spatial learning. Additionally, the R136S mutation reduced microglial interferon response to tau pathology both in vivo and in vitro , suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates the protective effects of R136S against tauopathy. ONE-SENTENCE SUMMARY: The R136S mutation on APOE3 enhances resistance to tau-related disease processes by downregulating the cGAS-STING-IFN signaling pathway.
