Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
Gillian Carling, Li Fan, Nessa Foxe, Kendra Norman, Man Ying Wong, Daphne Zhu, Carlo Corona, Agnese Razzoli, Fangmin Yu, Allan Yarahmady, Pearly Ye, Hao Chen, Yige Huang, Sadaf Amin, Rebecca Sereda, Chloe Lopez-Lee, Emmanouil Zacharioudakis, Xiaoying Chen, Jielin Xu, Feixiong Cheng, Evripidis Gavathiotis, Ana María Cuervo, David M. Holtzman, Sue‐Ann Mok, Subhash C. Sinha, Simone Sidoli, Rajiv R. Ratan, Wenjie Luo, Shiaoching Gong, Li Gan
Abstract
(R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. 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.