Nature neuroscience9/20/2023 While the transition is poorly understood, it coincides with alterations in innate immune responses, vasculature and metabolism 3. A long preclinical asymptomatic period with increasing deposition of amyloid-β plaques and tau aggregates transforms to a symptomatic phase with cognitive decline 1, 2, 3. 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.Īlzheimer’s disease (AD) is the most common late-onset dementia. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. 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. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. 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. ![]() Pathological hallmarks of Alzheimer’s disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. ![]() ![]() Nature Neuroscience volume 26, pages 737–750 ( 2023) Cite this article Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience
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