Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France.
FAES Farma, Leioa 48940, Spain.
Cell Rep. 2022 Aug 16;40(7):111200. doi: 10.1016/j.celrep.2022.111200.
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 κB (NF-κB) activation. We uncover that APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results in low-grade chronic inflammation and hyperactivated inflammatory responses. We show 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 brain of patients with sAD. Our findings highlight the APOE-TAGLN3-NF-κB axis regulating neuroinflammation in human astrocytes and reveal TAGLN3 as a molecular target to modulate neuroinflammation, as well as a potential biomarker for AD.
载脂蛋白 E4 (APOEε4) 是晚发性散发性阿尔茨海默病 (sAD) 的主要等位基因风险因素。炎症在 sAD 的发生和进展中被认为越来越关键。确定可以将这两个风险因素联系起来的大脑分子机制仍未阐明。利用诱导多能干细胞 (iPSC) 为基础的策略，我们证明 APOE 通过调节 Transgelin 3 (TAGLN3) 的表达，最终调节核因子 κB (NF-κB) 的激活，从而控制人类星形胶质细胞的炎症。我们发现 APOE4 特异性地下调 TAGLN3，涉及组蛋白去乙酰化酶的活性，从而导致低度慢性炎症和过度激活的炎症反应。我们表明 APOE4 通过 TAGLN3 补充以发挥一种显性负效应，使星形胶质细胞向促炎状态预先形成，这种状态可以通过药理学逆转。我们进一步证实 sAD 患者大脑中 TAGLN3 下调。我们的研究结果强调了 APOE-TAGLN3-NF-κB 轴在人类星形胶质细胞中调节神经炎症，并揭示了 TAGLN3 作为调节神经炎症的分子靶点，以及 AD 的潜在生物标志物。
