Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden.
Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden.
J Steroid Biochem Mol Biol. 2019 Jun;190:104-114. doi: 10.1016/j.jsbmb.2019.03.003. Epub 2019 Mar 13.
Alzheimer's disease (AD) is the most common form of dementia and it is characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. However, the complete pathogenesis of the disease is still unknown. High level of serum cholesterol has been found to positively correlate with an increased risk of dementia and some studies have reported a decreased prevalence of AD in patients taking cholesterol-lowering drugs. Years of research have shown a strong correlation between blood hypercholesterolemia and AD, however cholesterol is not able to cross the Blood Brain Barrier (BBB) into the brain. Cholesterol lowering therapies have shown mixed results in cognitive performance in AD patients, raising questions of whether brain cholesterol metabolism in the brain should be studied separately from peripheral cholesterol metabolism and what their relationship is. Unlike cholesterol, oxidized cholesterol metabolites known as oxysterols are able to cross the BBB from the circulation into the brain and vice-versa. The main oxysterols present in the circulation are 24S-hydroxycholesterol and 27-hydroxycholesterol. These oxysterols and their catalysing enzymes have been found to be altered in AD brains and there is evidence indicating their influence in the progression of the disease. This review gives a broad perspective on the relationship between hypercholesterolemia and AD, cholesterol lowering therapies for AD patients and the role of oxysterols in pathological and non-pathological conditions. Also, we propose cholesterol metabolites as valuable targets for prevention and alternative AD treatments.
阿尔茨海默病（AD）是最常见的痴呆症形式，其特征是大脑中淀粉样β（Aβ）斑块和神经原纤维缠结的沉积。然而，该疾病的完整发病机制仍不清楚。研究发现，血清胆固醇水平高与痴呆风险增加呈正相关，一些研究报告称，服用降胆固醇药物的患者 AD 的患病率降低。多年的研究表明，血液高胆固醇血症与 AD 之间存在很强的相关性，然而胆固醇不能穿过血脑屏障（BBB）进入大脑。降胆固醇疗法在 AD 患者的认知表现方面的结果喜忧参半，这引发了一个问题，即大脑中的胆固醇代谢是否应该与外周胆固醇代谢分开研究，以及它们之间的关系是什么。与胆固醇不同，氧化胆固醇代谢物（称为氧化固醇）能够从循环中穿过 BBB 进入大脑，反之亦然。循环中存在的主要氧化固醇是 24S-羟基胆固醇和 27-羟基胆固醇。已经发现这些氧化固醇及其催化酶在 AD 大脑中发生改变，并且有证据表明它们对疾病的进展有影响。这篇综述广泛探讨了高胆固醇血症与 AD、AD 患者的降胆固醇疗法以及氧化固醇在病理和非病理条件下的作用之间的关系。此外，我们还提出胆固醇代谢物作为预防和替代 AD 治疗的有价值的靶点。
