2. Academic Validation
  3. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience

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

  • Nat Neurosci. 2023 May;26(5):737-750. doi: 10.1038/s41593-023-01315-6.
Joe C Udeochu # 1,  Sadaf Amin # 2,  Yige Huang # 1,  Li Fan 1,  Eileen Ruth S Torres 1,  Gillian K Carling 1,  Bangyan Liu 1,  Hugo McGurran 3,  Guillermo Coronas-Samano 1,  Grant Kauwe 4,  Gergey Alzaem Mousa 1,  Man Ying Wong 1,  Pearly Ye 1,  Ravi Kumar Nagiri 1,  Iris Lo 3,  Julia Holtzman 3,  Carlo Corona 5,  Allan Yarahmady 6,  Michael T Gill 3,  Ravikiran M Raju 7 8,  Sue-Ann Mok 6,  Shiaoching Gong 1,  Wenjie Luo 1,  Mingrui Zhao 1,  Tara E Tracy 4,  Rajiv R Ratan 5,  Li-Huei Tsai 7,  Subhash C Sinha 1,  Li Gan 9
Affiliations

Affiliations

  • 1 Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
  • 2 Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • 3 The Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
  • 4 Buck Institute for Research on Aging, Novato, CA, USA.
  • 5 Burke Neurological Institute at Weill Cornell Medicine, White Plains, NY, USA.
  • 6 Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
  • 7 The Picower Institute of Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 8 Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 9 Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 37095396 DOI: 10.1038/s41593-023-01315-6
Abstract

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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