Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
Institute for Regenerative Medicine, University of Zürich, Zürich, Switzerland.
J Steroid Biochem Mol Biol. 2021 Jan;205:105785. doi: 10.1016/j.jsbmb.2020.105785. Epub 2020 Nov 7.
Altered cholesterol metabolism is associated with increased risk of neurodegeneration and in particular with the development of Alzheimer's disease (AD). Here, we investigate whether non-cholesterol sterols and oxysterols in the central nervous system are associated with (i) the presence of cerebral AD pathology, (ii) distinct aspects of AD pathology, i.e. amyloid pathology, neuronal injury, and tau pathology, and (iii) cognitive decline over time.
One hundred forty-two elder subjects with normal cognition, mild cognitive impairment, or mild dementia participating in a cohort study on cognitive decline and AD were included. Clinical and neuropsychological assessments were performed at inclusion and repeated at follow-up visits at 18 and 36 months. Concentrations of cholesterol, non-cholesterol sterols, and cholesterol metabolites were measured in cerebrospinal fluid (CSF), along with CSF beta-amyloid (Aβ); Aβ/Aβ ratio, total-tau (tau), and tau phosphorylated at threonine 181 (p-tau) as markers of amyloid pathology, neuronal injury and tau pathology, respectively. Cognitive decline was assessed by changes in Mini-Mental State Examination and Clinical Dementia Rating sum of boxes at follow-up visits.
CSF 24S-hydroxycholesterol (24S-OHC) and the 24S-OHC/27-OHC ratio were higher in subjects with AD pathology. CSF desmosterol correlated with Aβ levels. The 24S-OHC levels, the 24S-OHC/27-OHC ratio and the plant sterols campesterol and sitosterol were associated with the tau and p-tau levels. Both plant sterol concentrations along with the 24S-OHC/27-OHC ratio at baseline predicted cognitive decline at follow-up visits.
We show the importance of CSF levels of several non-cholesterol sterols and oxysterols to AD and core AD biomarkers. The plant sterols campesterol and sitosterol appear to be involved in tau pathology and neurodegeneration. CSF desmosterol level indicates CNS cholesterol synthesis and might be of relevance for clinical disease severity. Therefore these non-cholesterol sterols may represent intervention targets to slow down disease progression.
胆固醇代谢的改变与神经退行性变风险的增加有关，特别是与阿尔茨海默病（AD）的发展有关。在这里，我们研究中枢神经系统中的非胆固醇甾醇和氧化甾醇是否与（i）存在脑 AD 病理学，（ii）AD 病理学的不同方面，即淀粉样蛋白病理学、神经元损伤和 tau 病理学，以及（iii）随时间的认知下降有关。
本研究纳入了 142 名认知正常、轻度认知障碍或轻度痴呆的老年受试者，他们参加了一项关于认知下降和 AD 的队列研究。在纳入时进行临床和神经心理学评估，并在 18 个月和 36 个月的随访时重复评估。在脑脊液（CSF）中测量胆固醇、非胆固醇甾醇和胆固醇代谢物的浓度，以及 CSF 中的β-淀粉样蛋白（Aβ）；Aβ/Aβ 比值、总tau（tau）和 tau 磷酸化在苏氨酸 181 位（p-tau）分别作为淀粉样蛋白病理学、神经元损伤和 tau 病理学的标志物。认知下降通过随访时 Mini-Mental State Examination 和临床痴呆评定量表总分的变化来评估。
AD 病理学患者的 CSF 24S-羟胆固醇（24S-OHC）和 24S-OHC/27-OHC 比值较高。CSF 去甲胆固醇与 Aβ 水平相关。24S-OHC 水平、24S-OHC/27-OHC 比值以及植物甾醇胆甾醇和豆甾醇与 tau 和 p-tau 水平相关。基线时的植物甾醇浓度以及 24S-OHC/27-OHC 比值均预测随访时的认知下降。
我们表明，几种非胆固醇甾醇和氧化甾醇对 AD 和核心 AD 生物标志物的 CSF 水平很重要。植物甾醇胆甾醇和豆甾醇似乎参与了 tau 病理学和神经退行性变。CSF 去甲胆固醇水平表示中枢神经系统胆固醇合成，可能与临床疾病严重程度有关。因此，这些非胆固醇甾醇可能代表减缓疾病进展的干预靶点。
