(9/9) Our results show a new cell-autonomous mechanism to activate the IFN-I response in microglia. Interestingly, some PHD inhibitors are already in clinical use, and it would be interesting to see if they can improve microglial responses to Aß plaques.

(8/9) Mechanistically, FOXO3 –a transcriptional repressor of the IFN response– stability is regulated by PHD3. Interestingly, FOXO3 has been identified in human studies as a key factor in microglial responses doi.org/10.1016/j.ce..., and we now show that FOXO3 is associated with the IFN response.

(7/9) PHD3 deficiency correlates with a decrease in the AD microglia type-I IFN responses, decreased local Aß plaque pathology, and a rescue of the behavioral defects in AD mouse models.

(6/9) We now describe a new pathway that activates type-I IFN response in microglia controlled by HIF1 and PHD3, a transcriptional target of HIF1.

(5/9) Low oxygenation of the Aß plaques can be associated with local problems in angiogenesis www.nature.com/articles/s41...

(4/9) We have previously shown that Aß plaque-associated microglia have a strong HIF1-mediated response www.nature.com/articles/s43... @natmetabolism.nature.com

(3/9) It has been nicely demonstrated that microglial type-I IFN response is required for normal physiology and can be detrimental to the brain in chronic neurodegenerative diseases. The main controller of this response is the cGAS-STING pathway (see, for instance, www.cell.com/trends/neuro...

(2/9) We have characterized an unexpected cell-autonomous system to induce type-I interferon response in AD microglia.

Really happy to see our work on Alzheimer’s disease (AD) microglia published in @science.org www.science.org/doi/10.1126/.... A great work at IBiS from Manuel Sanchez-Garcia, Nieves Lara-Ureña, Rosana March-Diaz, @alicielena.bsky.social , and all our collaborators.