Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
Biochem Pharmacol. 2013 Jul 1;86(1):37-42. doi: 10.1016/j.bcp.2012.12.007. Epub 2013 Jan 3.
The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans. We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEε4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group. The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau.
阿尔茨海默病（AD）中描述的胆固醇合成和代谢紊乱可能既是神经退行性过程的结果，也是发病机制的促成因素。这些假定的关系及其潜在机制尚未得到很好的理解。本研究旨在评估人类大脑和脑外胆固醇合成和代谢与 AD 病理学（反映在 CSF 标志物中）之间的关系。我们评估了血浆和脑脊液（CSF）中胆固醇、胆固醇前体羊毛甾醇、菜油甾醇和去甲胆固醇以及胆固醇消除产物 24S-羟基胆固醇和 27-羟基胆固醇浓度与 CSF 中 AD 病理学标志物 Aβ1-42 和 p-tau181 在 86 名认知正常受试者和 107 名 AD 患者之间的关系。AD 组的 CSF 去甲胆固醇、胆固醇和 24S-羟基胆固醇，以及对照组的 CSF 24S-羟基胆固醇与 p-tau181 水平相关。所包括的化合物的 CSF 或血浆浓度均与 CSF Aβ1-42 水平无关。在包括年龄、性别、白蛋白比、载脂蛋白 Eε4 等位基因数和诊断在内的多变量回归测试中，p-tau181 水平独立预测了 CSF 去甲胆固醇、胆固醇和 24S-羟基胆固醇的浓度。当分别在 AD 组中进行分析时，CSF 胆固醇和 24S-羟基胆固醇的相关性仍然显著。这些结果表明，中枢神经系统胆固醇从头生成和代谢的改变与神经退行性变有关，特别是与大脑中磷酸化 tau 的积累有关。
