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. 2024 Dec 4;112(23):3877-3896.e8.
doi: 10.1016/j.neuron.2024.09.006. Epub 2024 Sep 30.

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

Gillian K Carling  1 , Li Fan  2 , Nessa R Foxe  1 , Kendra Norman  2 , Man Ying Wong  2 , Daphne Zhu  2 , Carlo Corona  3 , Agnese Razzoli  4 , Fangmin Yu  2 , Allan Yarahmady  5 , Pearly Ye  2 , Hao Chen  2 , Yige Huang  6 , Sadaf Amin  2 , Rebecca Sereda  7 , Chloe Lopez-Lee  1 , Emmanouil Zacharioudakis  8 , Xiaoying Chen  9 , Jielin Xu  10 , Feixiong Cheng  10 , Evripidis Gavathiotis  8 , Ana Maria Cuervo  7 , David M Holtzman  9 , Sue-Ann Mok  5 , Subhash C Sinha  2 , Simone Sidoli  8 , Rajiv R Ratan  3 , Wenjie Luo  2 , Shiaoching Gong  2 , Li Gan  11
Affiliations

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

Gillian K Carling et al. Neuron. .

Abstract

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 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 detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. 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.

Keywords: APOE; Alzheimer’s disease; R47H; TREM2; cGAS; inflammation; interferon; microglia; senescence; tau.

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Conflict of interest statement

Declaration of interests L.G. is founder and equity holder of Aeton Therapeutics, Inc. S.C.S. is an equity holder and a consultant of Aeton Therapeutics, Inc. L.G. is scientific co-founder of Neurovanda and consults for Retro Biosciences. D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid.

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