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CYCLIC GMP-AMP SYNTHASE PROMOTES MICROGLIAL INTERFERON ACTIVATION AND COGNITIVE DEFICITS IN TAUOPATHY.
Abstract
Aims
Alzheimer’s disease (AD) is the most common form of late-onset dementia. The striking enrichment of innate immune genes as risk alleles for AD points to microglial and innate immune signaling as important players in AD pathogenesis. Antiviral response pathways, which are upregulated in AD, have emerged as important regulators of microglial disease responses including immune activation and synaptic pruning. However, the specific mediators of maladaptive antiviral microglial responses in AD are still not understood. There is emerging evidence that cyclic GMP-AMP synthase (cGAS) DNA-sensing pathway drives deleterious type-I interferon activation in various neurodegenerative diseases. The role of this pathway in tauopathies and AD pathogenesis remains unexplored.
Methods
We apply combinatorial approaches to determine the effects of partial and complete loss of cGAS in the pathogenesis of the P301S tauopathy model. We utilize in vitro culture platforms, transcriptomics, electrophysiological recordings and behavioral assays to investigate the roles of cGAS in tauopathy.
Results
We find that cGAS and interferon signaling are activated in the hippocampi of tauopathy mice and AD patients. Loss of cGAS protects tauopathy mice from synapse loss, synaptic plasticity deficits and cognitive impairment. Additionally, we find that pathogenic tau induces a cGAS-dependent interferon-enriched microglial subpopulation in mice at least partly by causing mitochondrial DNA leakage. Pharmaceutical inhibition of cGAS ameliorates tau-induced synapse loss and cognitive deficits.
Conclusions
cGAS promotes deleterious microglial interferon activation implicated in synaptic dysfunction and cognitive impairment in tauopathy. The promising results of pharmacological cGAS inhibition in tauopathy mice supports cGAS as a potential therapeutic target for treating AD.