Статья

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Joe C. UdeochuHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USASadaf AminHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. [email protected]Yige HuangHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USALi FanHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAEileen Ruth S. TorresHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAGillian CarlingHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USABangyan LiuHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAHugo McGurranThe Gladstone Institute of Neurological Disease, San Francisco, CA, USAGuillermo Coronas‐SamanoHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAGrant KauweBuck Institute for Research on Aging, Novato, CA, USAGergey Alzaem MousaHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAMan Ying WongHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAPearly YeHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USANagiri Ravi KumarHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAIris LoThe Gladstone Institute of Neurological Disease, San Francisco, CA, USAJulia HoltzmanThe Gladstone Institute of Neurological Disease, San Francisco, CA, USACarlo CoronaBurke Neurological Institute at Weill Cornell Medicine, White Plains, NY, USAAllan YarahmadyDepartment of Biochemistry, University of Alberta, Edmonton, Alberta, CanadaMichael GillThe Gladstone Institute of Neurological Disease, San Francisco, CA, USARavikiran M. RajuDivision of Newborn Medicine, Boston Children's Hospital, Boston, MA, USASue‐Ann MokDepartment of Biochemistry, University of Alberta, Edmonton, Alberta, CanadaShiaoching GongHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAWenjie LuoHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USAMingrui ZhaoHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USATara E. TracyBuck Institute for Research on Aging, Novato, CA, USARajiv R. RatanBurke Neurological Institute at Weill Cornell Medicine, White Plains, NY, USALi‐Huei TsaiThe Picower Institute of Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USASubhash C. SinhaHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USALi GanHelen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. [email protected]

2023en

ABI

Аннотация

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.

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Идентификаторы

DOI: 10.1038/s41593-023-01315-6

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar