Koh Chor Hui Vivien, Cheung Nam Sang
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
Cell Signal. 2006 Nov;18(11):1844-53. doi: 10.1016/j.cellsig.2006.04.006. Epub 2006 May 7.
Neuronal cell death can occur by means of either necrosis or apoptosis. Both necrosis and apoptosis are generally believed to be distinct mechanisms of cell death with different characteristic features distinguished on the basis of their morphological and biochemical properties. The brain is the most cholesterol-rich organ in the body but not much is known about the mechanisms that regulate cholesterol homeostasis in the brain. Recently, several clinical and biochemical studies suggest that cholesterol imbalance in the brain may be a risk factor related to the development of neurological disorders such as Niemann-Pick disease type C (NPC) and Alzheimer's disease (AD). NPC is a fatal juvenile neurodegenerative disorder characterized by premature neuronal death and somatically altered cholesterol metabolism. The main biochemical manifestation in NPC is elevated intracellular accumulation of free cholesterol caused by a genetic deficit in cholesterol trafficking. The pharmacological agent, U18666A (3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one), is a well-known class-2 amphiphile which inhibits cholesterol transport. Cells treated with this agent accumulate intracellular cholesterol to massive levels, similar to that observed in cells from NPC patients. NPC and AD have some pathological similarities which may share a common underlying cause. AD is one of the most common types of dementia affecting the elderly. However, the molecular mechanisms of neurodegeneration in NPC and AD are largely unknown. This review provides a consolidation of work done using U18666A in the past half century and focuses on the implications of our research findings on the mechanism of U18666A-mediated neuronal apoptosis in primary cortical neurons, which may provide an insight to elucidate the mechanisms of neurodegenerative diseases, particularly NPC and AD, where apoptosis might occur through a similar mechanism.
神经元细胞死亡可通过坏死或凋亡的方式发生。坏死和凋亡通常被认为是不同的细胞死亡机制，基于其形态学和生化特性具有不同的特征。大脑是人体中胆固醇含量最高的器官，但关于调节大脑胆固醇稳态的机制我们知之甚少。最近，一些临床和生化研究表明，大脑中的胆固醇失衡可能是与诸如C型尼曼-匹克病（NPC）和阿尔茨海默病（AD）等神经疾病发展相关的一个风险因素。NPC是一种致命的青少年神经退行性疾病，其特征为神经元过早死亡和体细胞胆固醇代谢改变。NPC的主要生化表现是由于胆固醇转运的遗传缺陷导致细胞内游离胆固醇积累增加。药理试剂U18666A（3-β-[2-(二乙氨基)乙氧基]雄甾-5-烯-17-酮）是一种著名的2类两亲物，可抑制胆固醇转运。用该试剂处理的细胞会在细胞内积累大量胆固醇，类似于在NPC患者细胞中观察到的情况。NPC和AD有一些病理相似性，可能有共同的潜在病因。AD是影响老年人的最常见痴呆类型之一。然而，NPC和AD中神经退行性变的分子机制在很大程度上尚不清楚。本综述整合了过去半个世纪使用U18666A所做的工作，并聚焦于我们的研究结果对U18666A介导的原代皮质神经元凋亡机制的影响，这可能为阐明神经退行性疾病，特别是NPC和AD的机制提供见解，在这些疾病中凋亡可能通过类似机制发生。
