APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation
Résumé
Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer’s disease (sAD). Inflammation is increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two risk factors remain unelucidated. Leveraging induced pluripotent stem cell (iPSC)-based strategies, we demonstrate that APOE controls inflammation in human astrocytes by regulating Transgelin 3 (TAGLN3) expression and, ultimately, nuclear factor kB (NF-kB) activation. We uncover that APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results in low-gradechronicinflammationandhyperactivatedinflammatoryresponses.Weshow that APOE4 exerts a dominant negative effect to prime astrocytes toward a pro-inflammatory state that is pharmacologically reversible by TAGLN3 supplementation. We further confirm that TAGLN3 is downregulated in the brainofpatientswithsAD.OurfindingshighlighttheAPOE-TAGLN3-NF-kBaxisregulatingneuroinflammation in human astrocytes and reveal TAGLN3 as amolecular target to modulate neuroinflammation, as well as a potential biomarker for AD.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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