Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

Carling, G. K.; Fan, L.; Foxe, N. R.; Norman, K.; Ye, P.; Wong, M. Y.; Zhu, D.; Yu, F.; Xu, J.; Yarahmady, A.; Chen, H.; Huang, Y.; Amin, S.; Zacharioudakis, E.; Chen, X.; Holtzman, D. M.; Mok, S.-A. K.; Gavathiotis, E.; Sinha, S. C.; Cheng, F.; Luo, W.; Gong, S.; Gan, L.

doi:10.1101/2024.01.24.577107

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bioRxiv · 10.1101/2024.01.24.577107

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

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Abstract

The strongest risk factors for Alzheimers disease (AD) include the {chi}4 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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Carling, G. K., Fan, L., Foxe, N. R., Norman, K., Ye, P., Wong, M. Y., Zhu, D., Yu, F., Xu, J., Yarahmady, A., Chen, H., Huang, Y., Amin, S., Zacharioudakis, E., Chen, X., Holtzman, D. M., Mok, S.-A. K., Gavathiotis, E., Sinha, S. C., Cheng, F., Luo, W., Gong, S., Gan, L.. 2024-01-25. Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model. https://doi.org/10.1101/2024.01.24.577107

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