Molecular Signaling Laboratory, Monash University Central Clinical School, Department of Immunology, AMREP, Commercial Road, Melbourne, Victoria 3004, Australia.
Mol Cell Neurosci. 2010 Jan;43(1):33-42. doi: 10.1016/j.mcn.2009.07.013. Epub 2009 Aug 4.
Cholesterol, an essential component of cell membranes, plays an important role in the maintenance of cellular homeostasis and transmembrane communication within and between cellular compartments. In the brain that contains the highest levels of cholesterol in the body, cholesterol traffic occurs between nerve cells and between intracellular organelles in neurons to subserve normal brain function. Whereas glial cells produce the largest quantities of cholesterol, neurons also acquire cholesterol synthesized by astrocytes. The intracellular organelle endosomes and lysosomes receive and distribute cholesterol through the endocytic and retrograde transport pathways. However, deregulated cholesterol trafficking appears to be involved in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD) and Niemann-Pick disease type C (NPC) diseases. Under the pathological conditions of these neurodegenerative diseases, aberrant molecular interactions or particular depositions of cholesterol have been observed as critical causes to precipitate neuronal cell death. Here, we review the recent advances in terms of the role of cholesterol in healthy brain and molecular mechanisms of cholesterol involvement in AD, PD and NPC diseases. We discuss the different lines of evidence supporting different models of anomalous intracellular cholesterol trafficking with emphasis on cholesterol interactions with alpha-synuclein, NPC1 and NPC2 in AD, PD and NPC.
胆固醇是细胞膜的重要组成部分，在维持细胞内环境稳定和细胞内和细胞间的跨膜通讯方面发挥着重要作用。在体内胆固醇含量最高的大脑中，胆固醇在神经细胞之间以及神经元的细胞内细胞器之间进行运输，以维持正常的大脑功能。虽然神经胶质细胞产生的胆固醇最多，但神经元也可以从星形胶质细胞合成的胆固醇中获取。细胞内细胞器内体和溶酶体通过内吞作用和逆行运输途径接收和分配胆固醇。然而，胆固醇运输的失调似乎与阿尔茨海默病（AD）、帕金森病（PD）和尼曼-皮克病 C 型（NPC）等神经退行性疾病的发病机制有关。在这些神经退行性疾病的病理条件下，已经观察到胆固醇的异常分子相互作用或特定沉积是导致神经元细胞死亡的关键原因。在这里，我们综述了胆固醇在健康大脑中的作用以及胆固醇在 AD、PD 和 NPC 疾病中的作用的分子机制的最新进展。我们讨论了支持不同异常细胞内胆固醇运输模型的不同证据线，重点是胆固醇与 AD、PD 和 NPC 中的α-突触核蛋白、NPC1 和 NPC2 的相互作用。
