Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
J Alzheimers Dis. 2017;60(3):769-781. doi: 10.3233/JAD-160739.
Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.
To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.
Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.
Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.
hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.
载脂蛋白 E（ApoE）以其在脂质转运中的作用而闻名，ɛ4 等位基因是迟发性阿尔茨海默病（AD）的危险因素。最近，异常的神经酰胺和脂肪酸（FA）水平与 AD 有关。
确定人载脂蛋白 E4（hE4）在正常饮食或高脂肪/高胆固醇（HFHC）饮食对大脑神经酰胺和 FA 含量的具体影响。
通过 LC-MSMS 在 15 个月大的雌性野生型（WT）、载脂蛋白 E 敲除（E0）和 hE4 敲入小鼠中确定大脑神经酰胺和 FA 谱，这些小鼠分别在正常饮食或 HFHC 饮食下喂养 3 个月。通过 qPCR 确定参与神经酰胺和 FA 代谢的基因的 mRNA 水平。
与 E0 相似，hE4 小鼠在两种饮食下的大脑总神经酰胺、Cer16：0 和 Cer24：1 水平均低于 WT 小鼠。与 WT 小鼠相似，hE4 小鼠在正常饮食下的总和饱和 FA 水平低于 E0 小鼠。HFHC 饮食显著增加了 hE4 小鼠的总和饱和 FA 水平。在正常饮食下，hE4 小鼠的神经酰胺合酶（CerS）6、酸性鞘磷脂酶和大多数神经酰胺和 FA 转运蛋白的 mRNA 水平低于 WT 和 E0 小鼠。HFHC 饮食下调了 hE4 和 WT 小鼠的 CerS 表达，以及 WT 小鼠的神经酰胺和 FA 转运蛋白表达，但对 E0 小鼠没有影响。
hE4 降低了大脑神经酰胺水平，使其达到与 E0 小鼠在饮食无关的水平。HFHC 饮食增加了 hE4 小鼠大脑 FA 水平。这与 hE4 小鼠中特定的神经酰胺和 FA 转运蛋白表达的改变有关。
