Michikawa M, Yanagisawa K
Department of Dementia Research, National Institute for Longevity Sciences, Obu-Shi, Aichi, Japan.
Mech Ageing Dev. 1999 Mar 15;107(3):233-43. doi: 10.1016/s0047-6374(98)00134-1.
Apolipoprotein E (apoE) allele epsilon4 is a major risk factor for Alzheimer's disease (AD); however, the molecular mechanism underlying the acceleration of the development of AD in patients possessing epsilon4 remains to be determined. To investigate the isoform-specific effects of apoE on neurons, primary neuron cultures were prepared from fetal rat cerebral cortices. Inhibition of de novo cholesterol synthesis by compactin, a 3-hydroxyl-3-methylglutaryl CoA reductase inhibitor, induced neuronal cell death in a dose dependent manner. In the presence of a sublethal dose of compactin, apoE4 with beta-migrating very low density lipoproteins (beta-VLDL) caused apoptotic cell death in neuronal cultures. The same results were obtained with inhibition of de novo cholesterol synthesis by sublethal doses of squalestatin, an inhibitor of squalene synthase. The de novo cholesterol synthesis was suppressed to a higher degree by apoE4 than by apoE3, administered with beta-VLDL in the presence or absence of compactin. Mevalonate and squalene, which are metabolites of the cholesterol synthesis pathway, protected neuronal cells from apoE4-induced cell death. These results may suggest that apoE4 may exhibit neurotoxic action when de novo cholesterol synthesis is suppressed to a certain level, and that apoE4 induces neuronal cell death through the suppression of de novo cholesterol synthesis via an undetermined isoform-specific mechanism.
载脂蛋白E（apoE）ε4等位基因是阿尔茨海默病（AD）的主要危险因素；然而，携带ε4的患者中AD发病加速的分子机制仍有待确定。为了研究apoE对神经元的亚型特异性作用，从胎鼠大脑皮层制备了原代神经元培养物。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂洛伐他汀抑制从头胆固醇合成，以剂量依赖的方式诱导神经元细胞死亡。在亚致死剂量的洛伐他汀存在下，apoE4与β迁移极低密度脂蛋白（β-VLDL）一起导致神经元培养物中的凋亡细胞死亡。用亚致死剂量的角鲨烯合酶抑制剂角鲨他汀抑制从头胆固醇合成也得到了相同的结果。在存在或不存在洛伐他汀的情况下，与β-VLDL一起给药时，apoE4比apoE3更能抑制从头胆固醇合成。胆固醇合成途径的代谢产物甲羟戊酸和角鲨烯可保护神经元细胞免受apoE4诱导的细胞死亡。这些结果可能表明，当从头胆固醇合成被抑制到一定水平时，apoE4可能表现出神经毒性作用，并且apoE4通过一种未确定的亚型特异性机制抑制从头胆固醇合成来诱导神经元细胞死亡。
