cGAS-STING activation in Alzheimer´s disease
1 Clinical Neuroscience, Department of Neurology, University of Bonn, Bonn, Germany
2 M.Sc. Neurosciences, University of Antwerp, Antwerp, Belgium
3 German Center for Neurodegenerative Diseases, Bonn, Germany
Microglia are the resident immune cells in the CNS and play a key role in the inflammatory response commonly observed in neurodegenerative diseases such as Alzheimer’s disease (AD). The expression of multiple pattern recognition receptors allows them to detect changes in the environment and build up an inflammatory response. The cyclic guanosine monophosphate - adenosine monophosphate synthase (cGAS) detects double-stranded DNA in the cytoplasm, a sign of infection or self-DNA leakage due to cell damage. The product of this enzyme, 2´3´cGAMP, activates of the adaptor protein stimulator of interferon genes (STING, or TMEM173) leading to the production of type I interferons and pro-inflammatory cytokines. We hypothesize that this pathway can be activated during AD, affecting microglial function.
The analysis of cortex samples from post mortem AD patients revealed higher protein levels of STING when compared to control patients, as well as increased phosphorylation of IRF3. Similar results were obtained when analysing cortex samples of the amyloidosis mouse model APP/PS1 and wild type mice of 12 months. Immunohistochemical analysis of brain slices of these mice reveals STING localization within microglia. We have also observed decreased Aβ fibrils phagocytosis upon STING´s activation in vitro using THP-1 and primary microglial cells.
Altogether these results indicate that the cGAS-STING pathway could be involved in AD pathogenesis by affecting microglial function and points it as a potential target for new therapeutic treatments.