School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China.
School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China.
J Nutr Biochem. 2022 Aug;106:109016. doi: 10.1016/j.jnutbio.2022.109016. Epub 2022 Apr 18.
Cholesterol and its oxidative derivative 27-hydroxycholesterol (27-OHC), synthesized by CYP27A1, play an important role in Alzheimer's disease (AD) and phosphorylation of tau might be partly responsible for its pathogenesis. To investigate whether cholesterol and 27-OHC affected learning and memory through autophagy-mediated phosphorylation of tau, male C57BL/6J mice were administrated with 2% cholesterol diet, CYP27A1-short-hairpin RNA (CYP27A1-shRNA) and 3-methyladenine (3-MA). The results show that dietary cholesterol induces learning and memory impairment by upregulating the expression of brain CYP27A1 and increasing the levels of 27-OHC and 24S-hydroxycholesterol (24S-OHC). The expressions of total-tau (t-tau), phosphorylated-tau (p-tau) protein, glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5) are also significantly upregulated in this group. In addition, reduced expressions of Beclin-1 protein and microtubule-associated protein 1 light chain 3 (LC3B) mRNA, over-expression of mammalian target of rapamycin (mTOR) protein suggest that autophagy is impaired during cholesterol burden. However, using of CYP27A1-shRNA remarkably downregulates the expression of brain CYP27A1. Decreased 27-OHC levels in serum and brain, lower expressions of t-tau and p-tau protein are observed in mice treated with CYP27A1-shRNA+2% cholesterol diet. Furthermore, 3-MA causes lower Beclin-1, higher mTOR and p62 on both gene and protein levels, while the expression of t-tau, p-tau, GSK-3β and CDK5 are upregulated, demonstrating that impaired autophagy disturbs the clearance of tau. These findings suggest that dietary cholesterol induces the accumulation and phosphorylation of tau and the mechanism might be associated with impaired autophagy. And our results indicate 27-OHC might be an importance bridge between cholesterol and cognitive decline.
胆固醇及其氧化衍生物 27-羟胆固醇（27-OHC）由 CYP27A1 合成，在阿尔茨海默病（AD）中发挥重要作用，而 tau 的磷酸化可能部分与其发病机制有关。为了研究胆固醇和 27-OHC 是否通过自噬介导的 tau 磷酸化影响学习和记忆，雄性 C57BL/6J 小鼠给予 2%胆固醇饮食、CYP27A1-shRNA（CYP27A1-shRNA）和 3-甲基腺嘌呤（3-MA）。结果表明，饮食胆固醇通过上调脑 CYP27A1 的表达和增加 27-OHC 和 24S-羟胆固醇（24S-OHC）的水平，诱导学习和记忆障碍。总 tau（t-tau）、磷酸化 tau（p-tau）蛋白、糖原合成酶激酶-3β（GSK-3β）和周期蛋白依赖性激酶 5（CDK5）的表达也显著上调。此外，该组中 Beclin-1 蛋白和微管相关蛋白 1 轻链 3（LC3B）mRNA 的表达减少，哺乳动物雷帕霉素靶蛋白（mTOR）蛋白的表达增加，表明胆固醇负荷时自噬受损。然而，使用 CYP27A1-shRNA 可显著下调脑中 CYP27A1 的表达。用 CYP27A1-shRNA+2%胆固醇饮食处理的小鼠血清和脑中 27-OHC 水平降低，t-tau 和 p-tau 蛋白表达降低。此外，3-MA 在基因和蛋白水平上导致更低的 Beclin-1、更高的 mTOR 和 p62，而 t-tau、p-tau、GSK-3β 和 CDK5 的表达上调，表明自噬受损干扰 tau 的清除。这些发现表明，饮食胆固醇诱导 tau 的积累和磷酸化，其机制可能与自噬受损有关。我们的结果表明，27-OHC 可能是胆固醇与认知能力下降之间的重要桥梁。
