免疫原性微核激活cGAS-STING通路并影响PS1突变诱导Aβ形成的机制研究

PS1突变可导致早老性阿尔茨海默病（AD）并伴随着Aβ42(43)/Aβ40率的上升。PS1突变如何影响Aβ形成，是否涉及固有免疫，固有免疫又是如何调节Aβ则是远未清楚却又急需研究的科学问题。微核（MN）具有免疫原性（iMN），可激活cGAS-STING通路介导的固有免疫。AD患者的MN显著上升；我们发现敲低或过表达PS1显著增加人神经细胞MN，并据此提出PS1突变通过诱发iMN激活cGAS-STING通路进而影响Aβ形成的假说。课题以PS1敲除和转入致病性PS1突变的人神经细胞系为模型，利用遗传学、分子生物学和生物信息学研究手段，考察iMN形成、结构变化及其分子基础，研究cGAS-STING通路应答iMN以及对Aβ42(43)/Aβ40率的调节作用，探索抑制iMN的策略，以期较深入地阐明PS1突变激活iMN-cGAS-STING-Aβ信号轴的病理性作用，结果有望为AD早期干预提供新思路。

Presenilin-1 (PS1) mutations can cause familiar Alzheimer’s disease (AD) and is accompanied with an increased ratio of Aβ42(43)/Aβ40. How PS1 mutations influence the production of Aβ, whether innate immunity is involved in this process and how innate immunity regulates Aβ are scientific problems that are far from well understood and await further investigation urgently. The majority of newly-formed micronuclei (MN) are immunogenic (iMN) because micronuclear DNA is a cell intrinsic immuno-stimulatory molecule that triggers the cGAS-STING innate immune-sensing pathway and leads to pro-inflammatory response. AD patients possess a significant higher frequency of MN than that of healthy controls. Previously, we found that PS1 knockdown and over-expression resulted in significant increases in the frequency of MN in human neuron SH-SY5Y cells. In light of these findings, we hypothesize that PS1 mutations activate cGAS-STING innate pathway via inducing iMN, thereby increasing the Aβ42(43)/Aβ40 ratio. Here, using SH-SY5Y and human microglia HMC3 cells whose PS1 is knocked out or replaced by pathogenic mutations as the in vitro cell models, and using genetic, molecular biological and bioinformatic techniques as the main research methods, we aim to explore the biogenesis and structural alterations of iMN and the underlying mechanisms; investigate the surveillance roles of cGAS-STING pathway to iMN and the regulatory actions of cGAS-STING pathway to the Aβ42(43)/Aβ40 ratio; explore the potential ways that can inhibit the generation of iMN induced by PS1 mutations. This research project will helps to demonstrate the pathogenic mechanism of PS1 mutations through activating the iMN-cGAS-STING-Aβ signaling axis, and may provide new insights into the development of promising approaches for the intervention of early-stage AD.