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Updated: Aug 1, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience
Joe C Udeochu1, Sadaf Amin2, Yige Huang1
1Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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.
Insights
Cyclic GMP-AMP synthase (cGAS) activation reduces cognitive resilience in Alzheimer's disease (AD) by impairing the MEF2C network. Targeting this pathway may restore memory and synaptic function in AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) pathology precedes cognitive decline, highlighting a window of cognitive resilience.
- The mechanisms underlying this resilience and its disruption remain incompletely understood.
Purpose of the Study:
- To investigate the role of cyclic GMP-AMP synthase (cGAS) in diminishing cognitive resilience in Alzheimer's disease.
- To explore the cGAS-IFN-MEF2C signaling axis as a potential therapeutic target for AD.
Main Methods:
- Utilized mouse models of tauopathy with genetic ablation or pharmacological inhibition of cGAS.
- Assessed microglial type I interferon (IFN-I) responses, neuronal MEF2C expression, synapse integrity, plasticity, and cognitive function.
- Investigated the role of cytosolic mitochondrial DNA in activating cGAS.
Main Results:
- Activation of cGAS by pathogenic tau diminishes cognitive resilience by reducing the neuronal MEF2C network via IFN-I signaling.
- Genetic or pharmacological inhibition of cGAS preserved synapse integrity, plasticity, and cognitive function in tauopathic mice.
- cGAS ablation reduced microglial IFN-I responses and enhanced neuronal MEF2C expression without altering tau load.
Conclusions:
- The cGAS-IFN-MEF2C axis is a critical regulator of cognitive resilience in Alzheimer's disease.
- Targeting cGAS offers a promising therapeutic strategy to enhance resilience and restore cognitive function in AD.
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