APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation

• DOI: 10.1016/j.celrep.2022.111200
• Publication Date: 2022-08-16T14:44:56Z
• Authors: Laurie Arnaud; Philippe Benech; Louise Greetham; Delphine Stephan; Angélique Jimenez; Nicolas Jullien; Laura García-Gonz...; Philipp O. Tsvetkov; François Devred; Ignacio Sancho-Ma...; Juan Carlos Izpis...; Kévin Baranger; Santiago Rivera; Emmanuel Nivet
• Keywords: Apolipoprotein E

Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer's disease (sAD). Inflammation increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two factors remain unelucidated. Leveraging induced pluripotent stem cell (iPSC)-based strategies, we demonstrate APOE controls inflammation human astrocytes by regulating Transgelin 3 (TAGLN3) expression and, ultimately, nuclear κB (NF-κB) activation. We uncover APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results low-grade chronic hyperactivated inflammatory responses. show exerts a dominant negative effect to prime toward pro-inflammatory state pharmacologically reversible TAGLN3 supplementation. further confirm downregulated of patients with sAD. Our findings highlight APOE-TAGLN3-NF-κB axis neuroinflammation reveal target modulate neuroinflammation, well potential biomarker AD.