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.

大脑中胆固醇代谢的改变在阿尔茨海默病 (AD) 的生理学中发挥着重要作用。氧甾醇是胆固醇代谢物，对记忆功能和神经退行性疾病具有多种影响。先前的研究表明胆固醇代谢物对神经元有不利影响，但其对神经胶质细胞的影响尚不清楚。我们使用高脂肪/高胆固醇饮食的小鼠来研究高胆固醇血症对海马中警报素 S100A8 级联的影响。使用转基因小鼠模型 CYP27Tg，我们发现高胆固醇血症对大脑的影响是由过量的 27-羟基胆固醇 (27-OH)（一种胆固醇代谢物）介导的。我们还采用了脑室内注射 27-OH 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。我们报告称，高脂肪/高胆固醇饮食会导致大脑中 S100A8 的产生增加。在 CYP27Tg 中，我们报告在大脑中 27-OH 升高的情况下，海马中的 S100A8 及其受体 RAGE 增加。使用 siRNA，我们发现星形胶质细胞和神经元中 RAGE 27-OH 的上调是由核受体 RXRγ 介导的。沉默神经元中的 RXRγ 可阻止 27-OH 介导的 RAGE 上调。这些结果表明，S100A8 Alarmin 和 RAGE 通过 RXRγ 对大脑中神经元和星形胶质细胞中高水平的 27-OH 做出反应。我们的研究支持这样的观点：27-OH 通过警报信号传导介导高胆固醇血症对大脑的有害影响。