Seladin-1/DHCR24 protects neuroblastoma cells against Abeta toxicity by increasing membrane cholesterol content.
Seladin-1/DHCR24 protects neuroblastoma cells against Abeta toxicity by increasing membrane cholesterol content.
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DOI：
10.1111/j.1582-4934.2008.00216.x
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发表时间：
2008-10
影响因子：
5.3
通讯作者：
Stefani M
中科院分区：
文献类型：
--
作者：
Cecchi C;Rosati F;Pensalfini A;Formigli L;Nosi D;Liguri G;Dichiara F;Morello M;Danza G;Pieraccini G;Peri A;Serio M;Stefani M
脑胆固醇在阿尔茨海默病（AD）中的作用目前是一个有争议的问题。实验证据表明，降低循环和脑胆固醇可预防AD，但最近的数据表明，低膜胆固醇可导致神经变性，胆固醇合成催化剂seladin-1在AD影响的脑区域下调。我们之前报道了不同培养细胞类型对淀粉样蛋白毒性的抗性与膜胆固醇含量之间的显著相关性。在这里，我们提供的证据表明，Aβ42纤维前聚集体在过表达seladin-1或经过peg -胆固醇处理的人SH-SY5Y神经母细胞瘤细胞的质膜上积累的速度更慢，数量也更少。在使用特异性seladin-1抑制剂5,22e -cholestadien-3-ol或甲基-β-环糊精治疗后，胆固醇消耗细胞中的积累显著增加。暴露于Aβ42聚集体后，对淀粉样蛋白毒性的抗性和早期细胞质Ca2+升高分别通过增加膜胆固醇而增加和阻止，而在胆固醇耗尽的细胞中发现相反的作用。这些结果表明，seladin-1依赖性胆固醇合成减少了淀粉样蛋白诱导的胞质Ca2+失衡相关的膜-聚集体相互作用和细胞损伤。我们的研究结果扩展了最近报道的数据，表明seladin-1过表达直接增强了对a β毒性的抗性，这表明seladin-1/DHCR 24可能是散发性AD的新易感基因。
The role of brain cholesterol in Alzheimer's disease (AD) is currently a matter of debate. Experimental evidence suggests that reducing circulating and brain cholesterol protects against AD, however recent data indicate that low membrane cholesterol results in neurode-generation and that the cholesterol synthesis catalyst seladin-1 is down-regulated in AD-affected brain regions. We previously reported a significant correlation between resistance to amyloid toxicity and content of membrane cholesterol in differing cultured cell types. Here we provide evidence that Aβ42 pre-fibrillar aggregates accumulate more slowly and in reduced amount at the plasma membrane of human SH-SY5Y neuroblastoma cells overexpressing seladin-1 or treated with PEG-cholesterol than at the membrane of control cells. The accumulation was significantly increased in cholesterol-depleted cells following treatment with the specific seladin-1 inhibitor 5,22E-cholestadien-3-ol or with methyl-β-cyclodextrin. The resistance to amyloid toxicity and the early cytosolic Ca2+ rise following exposure to Aβ42 aggregates were increased and prevented, respectively, by increasing membrane cholesterol whereas the opposite effects were found in cholesterol-depleted cells. These results suggest that seladin-1-dependent cholesterol synthesis reduces membrane-aggregate interaction and cell damage associated to amyloid-induced imbalance of cytosolic Ca2+. Our findings extend recently reported data indicating that seladin-1 overexpression directly enhances the resistance to Aβ toxicity featuring seladin-1/DHCR 24 as a possible new susceptibility gene for sporadic AD.