Inactivation of the PHD3-FOXO3 axis blunts the type I interferon response in microglia and ameliorates Alzheimer’s disease progression

Microglia respond to Alzheimer’s disease (AD) with varied transcriptional responses. We show that oligomeric Aß (oAß) induces the expression of Hif1a and Egln3 in microglia in vitro, together with the transcription of the type I interferon signature (IFNS) genes in a PHD3-dependent manner. We identify FOXO3 as a repressor of IFNS, whose abundance decreases upon PHD3 induction in response to oAß. In vivo, loss of PHD3 correlates with abrogation of the IFNS and activation of the disease-associated microglia signature, an increase in microglia proximity to Aß plaques and phagocytosis of both Aß and small plaques. PHD3 deficiency mitigated the Aß plaque–associated neuropathology and rescued behavioral deficits of an AD mouse model. Last, we demonstrate that microglial PHD3 overexpression in the absence of Aß pathology is sufficient to induce the IFNS and behavioral alterations. Together, our data strongly indicate that the inactivation of the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, improving AD outcome.