Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden.
Mol Neurobiol. 2021 Dec;58(12):6063-6076. doi: 10.1007/s12035-021-02521-8. Epub 2021 Aug 27.
Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXRγ. Silencing RXRγ in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXRγ. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling.
胆固醇代谢在阿尔茨海默病（AD）的生理学中起着重要作用。氧化固醇是胆固醇代谢物，在记忆功能和神经退行性变中具有多种影响。先前的研究表明胆固醇代谢物对神经元有有害影响，但在神经胶质细胞中的作用尚不清楚。我们使用高脂肪/高胆固醇饮食在小鼠中研究了高胆固醇血症对海马体中警报素 S100A8 级联的影响。使用 CYP27Tg，一种转基因小鼠模型，我们表明，高胆固醇血症对大脑的影响是由胆固醇代谢物 27-羟胆固醇（27-OH）过量介导的。我们还采用了 27-OH 脑室注射的急性模型来研究 RAGE 和 S100A8 反应。我们使用神经元和星形胶质细胞的原代培养物来研究高水平 27-OH 对 S100A8 警报素级联的影响。我们报告说，高脂肪/高胆固醇饮食会导致大脑中 S100A8 的产生增加。在 CYP27Tg 中，我们报告说在大脑中 27-OH 升高时，海马体中的 S100A8 和其受体 RAGE 增加。使用 siRNA，我们发现 27-OH 上调星形胶质细胞和神经元中的 RAGE 是由核受体 RXRγ 介导的。在神经元中沉默 RXRγ 可防止 27-OH 介导的 RAGE 上调。这些结果表明，S100A8 警报素和 RAGE 通过 RXRγ 对神经元和星形胶质细胞中大脑中高水平的 27-OH 作出反应。我们的研究支持这样一种观点，即 27-OH 通过警报素信号转导介导高胆固醇血症对大脑的有害影响。
