Title | Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Carling GK, Fan L, Foxe NR, Norman K, Ye P, Wong MYing, Zhu D, Yu F, Xu J, Yarahmady A, Chen H, Huang Y, Amin S, Zacharioudakis E, Chen X, Holtzman DM, Mok S-A, Gavathiotis E, Sinha SC, Cheng F, Luo W, Gong S, Gan L |
Journal | bioRxiv |
Date Published | 2024 Jan 25 |
Abstract | The strongest risk factors for Alzheimer's disease (AD) include the χ4 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. |
DOI | 10.1101/2024.01.24.577107 |
Alternate Journal | bioRxiv |
PubMed ID | 38328219 |
PubMed Central ID | PMC10849737 |