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Updated: Jul 4, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a
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.
Insights
The strongest Alzheimer's disease risk factors, apolipoprotein E4 (APOE4) and TREM2 R47H, amplify microglial cGAS-STING signaling and senescence in female mice. This highlights potential drivers of Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Alzheimer's disease (AD) risk is influenced by genetic factors like apolipoprotein E (APOE) χ4 allele, TREM2 R47H variant, and female sex.
- Understanding synergistic effects of these risk factors is crucial for elucidating AD pathogenesis.
Approach:
- Investigated the combined impact of APOE4 and TREM2 R47H in female P301S tauopathy mouse models.
- Analyzed neurodegeneration, tau load, microglial signaling pathways (cGAS-STING), interferon response, and senescence.
- Examined the role of mitochondrial permeabilization in AD pathogenesis.
Key Points:
- The TREM2 R47H variant induced neurodegeneration in female APOE4 mice, independent of tau load.
- Combined APOE4 and R47H amplified tauopathy-induced microglial cGAS-STING signaling and type-I interferon responses.
- APOE4-R47H microglia showed increased senescence, linked to neurotoxic signatures and mitochondrial permeabilization.
Conclusions:
- The study identifies cGAS-STING signaling and microglial senescence as key pathways potentially driven by combined AD risk factors.
- These findings suggest novel therapeutic targets for Alzheimer's disease, particularly focusing on neuroinflammation and microglial function.
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