PT - JOURNAL ARTICLE AU - Laurie Arnaud AU - Philippe Benech AU - Louise Greetham AU - Delphine Stephan AU - Angélique Jimenez AU - Nicolas Jullien AU - Laura García-González AU - Philipp O. Tsvetkov AU - François Devred AU - Ignacio Sancho-Martinez AU - Juan-Carlos Izpisua Belmonte AU - Kevin Baranger AU - Santiago Rivera AU - Emmanuel Nivet TI - The Alzheimer’s disease risk factor APOE4 drives pro-inflammation in human astrocytes <em>via</em> HDAC-dependent repression of TAGLN3 AID - 10.1101/2021.04.16.440108 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.04.16.440108 4099 - http://biorxiv.org/content/early/2021/04/16/2021.04.16.440108.short 4100 - http://biorxiv.org/content/early/2021/04/16/2021.04.16.440108.full AB - The Apolipoprotein E4 (APOE4) is the major allelic risk factor for late-onset Alzheimer’s disease (AD). APOE4 associates with a pro-inflammatory phenotype increasingly considered as critical in AD initiation and progression. Yet, the mechanisms driving an APOE4-dependent neuroinflammation remain unelucidated. Leveraging patient specific human induced Pluripotent Stem Cells (iPSCs) we demonstrate inflammatory chronicity and hyperactivated responses upon cytokines in human APOE4 astrocytes via a novel mechanism. We uncovered that APOE4 represses Transgelin 3 (TAGLN3), a new interacting partner of IκBα, thus increasing the NF-kB activity. The transcriptional repression of TAGLN3 was shown to result from an APOE4-dependent histone deacetylase (HDAC) activity. The functional relevance of TAGLN3 was demonstrated by the attenuation of APOE4-driven neuroinflammation after TAGLN3 supplementation. Importantly, TAGLN3 downregulation was confirmed in the brain of AD patients. Our findings highlight the APOE4-TAGLN3 axis as a new pathogenic pathway that paves the way for the development of therapeutics to prevent maladaptive inflammatory responses in APOE4 carriers, while placing TAGLN3 downregulation as a potential biomarker of AD.Competing Interest StatementThe authors have declared no competing interest.