Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
Gillian CarlingHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USALi FanHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USANessa FoxeHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USAKendra NormanHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USAMan Ying WongHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USADaphne ZhuHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USACarlo CoronaBurke Neurological Institute, Weill Cornell Medicine, White Plains, NY 10605, USAAgnese RazzoliTransfusion Medicine Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia 42122, Italy; Clinical and Experimental PhD Program, University of Modena and Reggio Emilia, Modena 41121, ItalyFangmin YuHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USAAllan YarahmadyDepartment of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaPearly YeHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USAHao ChenHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USAYige HuangHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Biochemistry, Structural Biology, Cell Biology, Developmental Biology, and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USASadaf AminMIND Research InstituteRebecca SeredaDepartment of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USAChloe Lopez-LeeHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USAEmmanouil ZacharioudakisDepartment of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USAXiaoying ChenDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USAJielin XuCleveland Clinic Genome Center and Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USAFeixiong ChengCleveland Clinic Genome Center and Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USAEvripidis GavathiotisDepartment of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USAAna María CuervoDepartment of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USADavid M. HoltzmanDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USASue‐Ann MokDepartment of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaSubhash C. SinhaHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USASimone SidoliDepartment of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USARajiv R. RatanBurke Neurological Institute, Weill Cornell Medicine, White Plains, NY 10605, USAWenjie LuoHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USAShiaoching GongHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USALi GanHelen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: [email protected]
2024en
ABI
Аннотация
(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.
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