PDF(Pubmed)
Abstract：
The Christchurch mutation (R136S) on the APOE3 (E3S/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 carrier1. However, the molecular effects enabling E3S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3S/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.
摘要：
APOE3（E3S/S）基因上的克赖斯特彻奇突变（R136S）与低tau病理和认知下降的减慢有关，尽管PSEN1突变和载体1中高水平的淀粉样蛋白β病理。然而,使E3S/S突变产生保护作用的分子效应尚不清楚.这里,我们在tau病变背景下用野生型人类E3或EDS/S代替了小鼠Apoe。R136S突变可显着减轻tau负荷并防止tau诱导的突触损失，髓鞘丢失,空间学习。此外,R136S突变在体内和体外都降低了小胶质干扰素对tau病理的反应，抑制cGAS-STING激活。用cGAS抑制剂治疗携带野生型E3的tau蛋白病小鼠可防止tau诱导的突触损失，并诱导与R136S突变诱导的类似的转录组改变。因此，cGAS-STING-IFN抑制概括了R136S对tau蛋白病的保护作用。
■APOE3上的R136S突变通过下调cGAS-STING-IFN信号通路来增强对tau相关疾病过程的抗性。
■APOE3上的R136S突变通过下调cGAS-STING-IFN信号通路来增强对tau相关疾病过程的抗性。
