biostudies-literatureUnknown11(22)Sanchez-Garcia MAMicroglia respond to Alzheimer's disease (AD) with varied transcriptional responses. We show that oligomeric Aß (oAß) induces the expression of <i>Hif1a</i> and <i>Egln3</i> 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 overexScience advanceseadu2244https://www.ebi.ac.uk/biostudies/studies/S-EPMC12118632biostudies-literatureInactivation of the PHD3-FOXO3 axis blunts the type I interferon response in microglia and ameliorates Alzheimer's disease progression.PMC12118632Barba-Reyes JMMunoz-Manchado ABRosales-Nieves AEOrtega-de San Luis CMunoz-Cabello AMLopez-Barneo JVizuete MMarch-Diaz RHeras-Garvin ANavarro VMora-Romero BSanchez-Garcia MARomero-Molina CQuinones-Canete SPascual ACokman MEVitorica JLara-Urena NCabello-Rivera DfalseInactivation 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 <i>Hif1a</i> and <i>Egln3</i> 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 overex2025-01-01T00:00:00Z2025 May2026-06-02T20:33:56.287Z2026-05-27T03:07:58.38ZS-EPMC121186324043526010.1126/sciadv.adu2244