Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease
Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease
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DOI：
10.1073/pnas.0305799101
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发表时间：
2004-02-17
影响因子：
11.1
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Cutler, RG;Kelly, J;Mattson, MP
阿尔茨海默病(AD)是一种年龄相关性疾病，以淀粉样β蛋白(Abeta)沉积和海马区等脑区神经元变性为特征，导致进行性认知功能障碍。阿尔茨海默病的发病机制与Abeta沉积和氧化应激密切相关，但这些因素如何导致神经元功能障碍和死亡仍不清楚。我们报告了正常脑老化和AD患者大脑中鞘磷脂和胆固醇代谢的变化，这些变化导致长链神经酰胺和胆固醇的积累。膜相关的氧化应激与脂质改变有关，海马神经元暴露于Abeta可诱导膜氧化应激，神经酰胺类物质和胆固醇的积累。用α-生育酚或鞘磷脂合成抑制剂治疗神经元可以防止神经酰胺和胆固醇的积累，并保护它们免受Abeta诱导的死亡。我们的发现提示了AD发病机制中的一系列事件，其中Abeta诱导膜相关的氧化应激，导致神经酰胺和胆固醇代谢紊乱，进而触发神经退行性级联反应，导致临床疾病。
Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid beta-peptide (Abeta) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Abeta deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Abeta induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with alpha-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Abeta. Our findings suggest a sequence of events in the pathogenesis of AD in which Abeta induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.