The Role of Brain Cholesterol and its Oxidized Products in Alzheimer's Disease
The Role of Brain Cholesterol and its Oxidized Products in Alzheimer's Disease
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DOI：
10.2174/1567205012666150921103426
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发表时间：
2016-01-01
影响因子：
2.1
通讯作者：
Gaetani, Silvana
中科院分区：
文献类型：
--
作者：
Giudetti, Anna Maria;Romano, Adele;Gaetani, Silvana
人脑是胆固醇含量最丰富的器官，占全身胆固醇总量的25%。中枢神经系统 (CNS) 中的胆固醇几乎完全来自内源性合成，循环中的胆固醇无法穿过血脑屏障 (BBB)。在这个过程中，星形胶质细胞似乎比神经元更活跃。神经元主要依赖附近细胞的胆固醇传递来进行轴突再生、神经突延伸和突触发生。在大脑内，胆固醇由与 apoE 相关的 HDL 样脂蛋白运输，apoE 代表中枢神经系统中的主要载脂蛋白。尽管中枢神经系统胆固醇含量在很大程度上与饮食摄入或肝脏合成无关，但血浆胆固醇水平与神经退行性疾病（如阿尔茨海默病 (AD)）之间的关系经常被报道。在这方面，胆固醇代谢的改变被认为与 AD 的病因学和大脑中淀粉样蛋白的产生有关。因此，人们特别关注控制大脑中胆固醇代谢的主要因素的研究。大脑胆固醇水平受到严格控制：通过转化为氧化形式的24-S-羟基胆甾醇（24-OH-C）可以减少过量的胆固醇，该形式可以到达血液。事实上，血脑屏障可渗透24-OH-C以及主要由非神经细胞合成的另一种氧化形式的胆固醇27-OH-C。在这篇综述中，我们总结了调节胆固醇稳态的主要机制，并回顾了胆固醇和胆固醇氧化产物在AD中所起作用的最新进展。此外，我们描述了通过影响胆固醇稳态来控制 AD 进展的可能药理学策略。
The human brain is the most cholesterol-rich organ harboring 25% of the total cholesterol pool of the whole body. Cholesterol present in the central nervous system (CNS) comes, almost entirely, from the endogenous synthesis, being circulating cholesterol unable to cross the blood-brain barrier (BBB). Astrocytes seem to be more active than neurons in this process. Neurons mostly depend on cholesterol delivery from nearby cells for axonal regeneration, neurite extension and synaptogenesis. Within the brain, cholesterol is transported by HDL-like lipoproteins associated to apoE which represents the main apolipoprotein in the CNS.Although CNS cholesterol content is largely independent of dietary intake or hepatic synthesis, a relationship between plasma cholesterol level and neurodegenerative disorders, such as Alzheimer's disease (AD), has often been reported. To this regard, alterations of cholesterol metabolism were suggested to be implicated in the etiology of AD and amyloid production in the brain. Therefore a special attention was dedicated to the study of the main factors controlling cholesterol metabolism in the brain.Brain cholesterol levels are tightly controlled: its excessive amount can be reduced through the conversion into the oxidized form of 24-S-hydroxycholesetrol (24-OH-C), which can reach the blood stream. In fact, the BBB is permeable to 24-OH-C as well as to 27-OH-C, another oxidized form of cholesterol mainly synthesized by non-neural cells.In this review, we summarize the main mechanisms regulating cholesterol homeostasis and review the recent advances on the role played by cholesterol and cholesterol oxidized products in AD. Moreover, we delineate possible pharmacological strategies to control AD progression by affecting cholesterol homeostasis.