陶氏病
神经退行性变
特雷姆2
小胶质细胞
生物
神经炎症
衰老
神经科学
阿尔茨海默病
细胞生物学
疾病
免疫学
医学
炎症
内科学
作者
Gillian Carling,Li Fan,Nessa Foxe,Keri N. Norman,Pearly Ye,Man Ying Wong,Daphne Zhu,Fangmin Yu,Jielin Xu,Allan Yarahmady,Hao Chen,Yige Huang,Sadaf Amin,Emmanouil Zacharioudakis,Xiaoying Chen,David M. Holtzman,Sue-Ann Mok,Evripidis Gavathiotis,Subhash C. Sinha,Feixiong Cheng,Wenjie Luo,Shiaoching Gong,Li Gan
标识
DOI:10.1101/2024.01.24.577107
摘要
The strongest risk factors for Alzheimer's disease (AD) include the ϵ4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.
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