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bioRxiv · 10.1101/2021.04.16.440108

The Alzheimer's disease risk factor APOE4 drives pro-inflammation in human astrocytes via HDAC-dependent repression of TAGLN3

Arnaud, L.·Benech, P.·Greetham, L.·Stephan, D.·Jimenez, A.·Jullien, N.·Garcia-Gonzalez, L.·Tsvetkov, P. O.·Devred, F.·Sancho-Martinez, I.·Belmonte, J. C. I.·Baranger, K.·Rivera, S.·Nivet, E.
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Abstract

The Apolipoprotein E4 (APOE4) is the major allelic risk factor for late-onset Alzheimers 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 I{kappa}B, 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=98 HEIGHT=200 SRC="FIGDIR/small/440108v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1036557org.highwire.dtl.DTLVardef@1f245bdorg.highwire.dtl.DTLVardef@c07c4aorg.highwire.dtl.DTLVardef@1200396_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Arnaud, L., Benech, P., Greetham, L., Stephan, D., Jimenez, A., Jullien, N., Garcia-Gonzalez, L., Tsvetkov, P. O., Devred, F., Sancho-Martinez, I., Belmonte, J. C. I., Baranger, K., Rivera, S., Nivet, E.. 2021-04-16. The Alzheimer's disease risk factor APOE4 drives pro-inflammation in human astrocytes via HDAC-dependent repression of TAGLN3. https://doi.org/10.1101/2021.04.16.440108

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