Huynh Thao N, Fikse Emma N, De La Torre Adrianna L, Havrda Matthew C, Chang Catherine C Y, Chang Ta Yuan
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Department of Molecular and System Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Int J Mol Sci. 2024 Dec 21;25(24):13690. doi: 10.3390/ijms252413690.
Aging and apolipoprotein E4 () are the two most significant risk factors for late-onset Alzheimer's disease (LOAD). Compared to , disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells, including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate -dependent phenotypes. Toll-like receptor 4 (TLR4) is a key macromolecule in inflammation, and its regulation is associated with the cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. This study found that treating primary microglia expressing with F12511 also reduces CEs, activates ABCA1, and dampens LPS-dependent NFκB activation. In vivo, two-week injections of nanoparticle F12511, which consists of DSPE-PEG, phosphatidylcholine, and F12511, to aged female mice reduced TLR4 protein content and decreased proinflammatory cytokines, including IL-1β in mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.
衰老和载脂蛋白E4（ApoE4）是晚发性阿尔茨海默病（LOAD）的两个最重要的风险因素。与ApoE3相比，ApoE4会破坏胆固醇稳态，增加胆固醇酯（CEs），并加剧包括小胶质细胞在内的脑细胞中的神经炎症。针对CEs和神经炎症可能是改善ApoE4相关表型的一种新策略。Toll样受体4（TLR4）是炎症中的关键大分子，其调节与细胞膜脂筏中的胆固醇含量有关。我们之前证明，在表达APOE3的正常小胶质细胞中，抑制胆固醇储存酶酰基辅酶A：胆固醇酰基转移酶1（ACAT1/SOAT1）可减少CEs，通过调节TLR4的命运来减轻神经炎症。我们还表明，用ACAT抑制剂F12511处理负载髓磷脂碎片的正常小胶质细胞可降低细胞内CEs，并激活ATP结合盒转运蛋白1（ABCA1）以促进胆固醇外流。本研究发现，用F12511处理表达ApoE4的原代小胶质细胞也可减少CEs，激活ABCA1，并抑制脂多糖（LPS）依赖性核因子κB（NFκB）的激活。在体内，对老年雌性ApoE4小鼠注射由二硬脂酰磷脂酰乙醇胺-聚乙二醇（DSPE-PEG）、磷脂酰胆碱和F12511组成的纳米颗粒F12511两周，可降低小鼠大脑中TLR4蛋白含量，并减少促炎细胞因子，包括白细胞介素-1β（IL-1β）。总体而言，我们的研究表明纳米颗粒F12511是一种改善LOAD的新型药物。
