College of Pharmacy, Heilongjiang University of Chinese Medicine, 150040 Harbin, Heilongjiang, China.
Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, 214071 Wuxi, Jiangsu, China.
Actas Esp Psiquiatr. 2024 Oct;52(5):641-652. doi: 10.62641/aep.v52i5.1723.
The pathogenesis of Alzheimer's disease (AD) is complex. Recent research suggests that AD patients have early disorders in brain cholesterol metabolism. Cholesterol and its derivatives accumulate in neurons, leading to p-Tau overproduction and synaptic dysfunction, initiating AD progression. Calycosin-7-O-β-D-glucoside (CG), a distinctive constituent of Astragali Radix, holds a representative position. Many clinical trials have demonstrated that CG can attenuate cerebral ischemia/reperfusion injury and preserve the structural integrity of the blood-brain barrier. However, whether CG alleviates tau-mediated neurodegeneration by increasing cholesterol efflux after lipid accumulation remains unexplored.
Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and multivariate data analysis were employed to investigate metabolic changes in HT22 cells induced by sodium palmitate following 24 hours of CG treatment. The potential therapeutic mechanisms of CG on AD were further examined through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.
Metabolomic analysis characterized 24 potential biomarkers, revealing that CG could ameliorate cholesterol metabolic pathways. The results of cell experiments revealed that CG can increase the expression of enzyme cholesterol 24-hydroxylase (CYP46A1) (p < 0.05) and the level of 24 hydroxycholesterol (24-OHC) (p < 0.05), reduce the expression of p-Tau (Thr231)/Tau (p < 0.01), inhibit the formation of lipid droplets.
CG may inhibit the accumulation of cholesterol and its derivatives in neurons by affecting the CYP46A1-CE-Tau axis, offering a potential therapeutic strategy for AD.
阿尔茨海默病（AD）的发病机制复杂。最近的研究表明，AD 患者的脑胆固醇代谢早期出现紊乱。胆固醇及其衍生物在神经元中蓄积，导致 p-Tau 过度产生和突触功能障碍，从而启动 AD 的进展。毛蕊异黄酮-7-O-β-D-葡萄糖苷（CG）是黄芪的特有成分，具有代表性。许多临床试验表明 CG 可以减轻脑缺血/再灌注损伤，保持血脑屏障的结构完整性。然而，CG 是否通过增加脂质积累后的胆固醇外排来缓解 tau 介导的神经退行性变，目前仍不清楚。
采用超高效液相色谱/四极杆飞行时间质谱（UPLC-Q-TOF-MS/MS）和多元数据分析方法，研究 CG 处理 HT22 细胞 24 小时后，棕榈酸钠诱导的 HT22 细胞代谢变化。通过京都基因与基因组百科全书（KEGG）通路富集分析进一步研究 CG 对 AD 的潜在治疗机制。
代谢组学分析鉴定了 24 个潜在的生物标志物，表明 CG 可以改善胆固醇代谢途径。细胞实验结果表明，CG 可以增加酶胆固醇 24-羟化酶（CYP46A1）的表达（p<0.05）和 24-羟胆固醇（24-OHC）的水平（p<0.05），降低 p-Tau（Thr231）/Tau 的表达（p<0.01），抑制脂滴的形成。
CG 可能通过影响 CYP46A1-CE-Tau 轴来抑制神经元中胆固醇及其衍生物的蓄积，为 AD 提供一种潜在的治疗策略。
