Petanceska Suzana S, DeRosa Steven, Sharma Ali, Diaz Nichole, Duff Karen, Tint Steven G, Refolo Lorenzo M, Pappolla Miguel
Center for Dementia Research, Nathan Kline Institute, Orangeburg NY 10962, USA.
J Mol Neurosci. 2003;20(3):395-406. doi: 10.1385/JMN:20:3:395.
Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer's disease (AD) in an isoform-dependent manner, such that the presence of the apoE epsilon4 allele increases the risk of AD while the presence of the apoE epsilon2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the "risk factor" activity of AD, its ability to bind amyloid beta peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Abeta accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer's amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.
载脂蛋白E（ApoE）以异构体依赖的方式影响晚发型阿尔茨海默病（AD）的风险，即载脂蛋白Eε4等位基因的存在会增加AD的风险，而载脂蛋白Eε2等位基因的存在似乎具有保护作用。尽管许多ApoE功能是异构体依赖的，可能是AD“风险因素”活性的基础，但其结合淀粉样β肽并影响其清除和/或沉积的能力已获得有力的实验支持。有证据表明，除了基因型外，ApoE转录增加也可能导致AD风险。越来越多的证据支持胆固醇代谢紊乱是AD早期风险因素这一假说。动物模型研究表明，胆固醇代谢的长期变化与脑内淀粉样蛋白β（Aβ）积累的变化相关，这一过程对建立AD病理至关重要。ApoE介导体内胆固醇稳态，是脑内主要的脂质载体。因此，其在外周和脑内的表达会随着胆固醇代谢的变化而改变。在此，我们使用阿尔茨海默病淀粉样变性转基因小鼠模型，来研究饮食诱导或药物诱导的血浆胆固醇变化导致脑淀粉样变性改变时，是否也会影响肝脏和脑内的ApoE含量。我们发现，血浆总胆固醇的长期变化会导致脑内ApoE mRNA水平的改变。我们还发现，原代神经胶质细胞的胆固醇负荷会增加细胞内和分泌的ApoE水平，而用他汀类药物长期处理星形胶质细胞和小胶质细胞会导致细胞内和/或分泌的ApoE减少。这些观察结果表明，胆固醇代谢紊乱可能部分由于胆固醇对脑内ApoE表达的影响而增加患AD的风险。
