The latest study from the Gan Lab, published in Nature Neuroscience, revealed a striking contribution of cGAS-interferon-MEF2C network to tau-induced neurotoxicities in Alzheimer’s disease and related disorders. They found that tau-activation of cGAS in AD diminishes cognitive resilience by decreasing the neuronal transcriptional network of MEF2C through type I interferon (IFN-I) signaling.
The study was led by Dr. Sadaf Amin, Yige (Gloria) Huang, and Dr. Joe Udeochu in the Gan laboratory, in collaboration with Appel Institute faculty Drs. Subhash Sinha and Wenjie Luo, in addition to Drs. Li Huei Tsai at the Picower Institute of Learning and Memory at MIT, Tara Tracy at the Buck Institute for Research on Aging, Rajiv Ratan at the Burke Neurological Institute at Weill Cornell Medicine, and Sue-Ann Mok at the University of Alberta.
The authors found that in microglia, engulfed pathogenic tau enters mitochondria and triggers mtDNA release into the cytosol which activates IFN-I responses in a cGAS-dependent manner. Genetic ablation of cGAS in tauopathy mice diminished microglial IFN-I, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. In neurons, this resilient phenotype was accompanied by a significant upregulation of transcriptional network of MEF2C- an AD cognitive resilience gene- in an IFN-dependent manner. cGAS ablation enhanced, while activation of IFN-I downregulated, neuronal MEF2C network. Furthermore, pharmacological inhibition of cGAS in tauopathy mice enhanced neuronal MEF2C network and restored synaptic integrity, plasticity, and memory. These data strongly support the therapeutic potential of targeting cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.
Read the full paper HERE. The WCM Newsroom press release can be read HERE.