The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway Journal Article


Authors: Naguib, S.; Lopez-Lee, C.; Torres, E. R.; Lee, S. I.; Zhu, J.; Zhu, D.; Ye, P.; Norman, K.; Zhao, M.; Wong, M. Y.; Ambaw, Y. A.; Muñoz-Castañeda, R.; Wang, W.; Patel, T.; Bhagwat, M.; Norinsky, R.; Mok, S. A.; Walther, T. C.; Farese, R. V. Jr; Luo, W.; Sinha, S. C.; Wu, Z.; Fan, L.; Gong, S.; Gan, L.
Article Title: The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway
Abstract: The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse Apoe with wild-type human APOE3 or APOE3S/S on a tauopathy background. The R136S mutation decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in hippocampal theta and gamma power. Additionally, the R136S mutation reduced interferon responses to tau pathology in both mouse and human microglia, suppressing cGAS-STING pathway activation. Treating E3 tauopathy mice with a cGAS inhibitor protected against tau-induced synaptic loss and induced transcriptomic alterations similar to the R136S mutation across brain cell types. Thus, suppression of the microglial cGAS-STING-interferon (IFN) pathway plays a central role in mediating the protective effects of R136S against tauopathy. © 2025 Elsevier Inc.
Keywords: interferon; neurodegeneration; microglia; tauopathy; apoe; cgas; alzheimer's; christchurch; local field potentials; single-nuclei rna sequencing
Journal Title: Immunity
Volume: 58
Issue: 8
ISSN: 1074-7613
Publisher: Cell Press  
Publication status: Published
Date Published: 2025-08-12
Online Publication Date: 2025-06-23
Start Page: 1931
End Page: 1947.e9
Language: English
DOI: 10.1016/j.immuni.2025.05.023
PROVIDER: scopus
PUBMED: 40555238
PMCID: PMC12406129
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Robert V Farese
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  2. Yohannes Abere Ambaw
    4 Ambaw