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Cited by 89Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Carling, Gillian K., Fan, Li, Foxe, Nessa R., Norman, Kendra, Wong, Man Ying, Zhu, Daphne, Corona, Carlo, Razzoli, Agnese +22 more·2024·Neuron
DOI 10.1016/j.neuron.2024.09.006PMC PMC11624100

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Abstract

SUMMARY 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.

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  • ApoE4 is the strongest genetic risk factor for sporadic, late-onset Alzheimer's disease and is associated with neurodegeneration, neuronal damage, and tau phosphorylation.

    “ApoE4 is the strongest genetic risk factor for sporadic, late-onset Alzheimer’s disease and is associated with neurodegeneration, neuronal damage, and tau phosphorylation [25].”

    From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [25]

    The Introduction (page not provided) calls APOE4 the strongest genetic risk factor for late-onset AD and links it to tau toxicity and neurodegeneration. The Results (page not provided) report increased hyperphosphorylated tau and synaptic loss in female tauopathy mice with both APOE4 and TREM2 R47H; they do not establish those effects for APOE4 alone, as the citing sentence implies. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Carling, G. K., Fan, L., Foxe, N. R., Norman, K., Wong, M. Y., Zhu, D., Corona, C., Razzoli, A., Yu, F., Yarahmady, A., Ye, P., Chen, H., Huang, Y., Amin, S., Sereda, R., Lopez-Lee, C., Zacharioudakis, E., Chen, X., Xu, J., Cheng, F., Gavathiotis, E., Cuervo, A. M., Holtzman, D. M., Mok, S.-A., Sinha, S. C., Sidoli, S., Ratan, R. R., Luo, W., Gong, S., & Gan, L.
Affiliations
  • Weill Cornell Medicine (US)
  • University of Modena and Reggio Emilia (IT)
  • University of Alberta (CA)
  • Albert Einstein College of Medicine (US)
  • Washington University in St. Louis (US)
  • Cleveland Clinic (US)
Corresponding author
Gan, Li
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2024-12
Volume
112
Issue
23
Pages
3877-3896.e8
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2024.09.006
PMC
PMC11624100
OpenAlex
W4402966636
Cited by
89
References
46
Citations by year
2026: 53 · 2025: 30 · 2024: 6
FWCI
22.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
Funders
  • BrightFocus Foundation
  • Rainwater Charitable Foundation
  • Foundation for the National Institutes of Health
  • Cure Alzheimer's Fund
  • National Institute on Aging
  • American Foundation for Aging Research
  • Jumpstart
  • JPB Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, APOE ε4, tauopathy, microglial senescence, cGAS-STING pathway, interferon response, neurodegeneration, hyperphosphorylated tau, mitochondrial membrane permeabilization, Bax, neuroinflammation

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