Abstract：
APOE4 encoding apolipoprotein (Apo)E4 is the strongest genetic risk factor for Alzheimer\'s disease (AD). ApoE is key in intercellular lipid trafficking. Fatty acids are essential for brain integrity and cognitive performance and are implicated in neurodegeneration. We determined the sex- and age-dependent effect of AD and APOE4 on brain free fatty acid (FFA) profiles. FFA profiles were determined by LC-MS/MS in hippocampus, cortex, and cerebellum of female and male, young (≤3 months) and older (>5 months), transgenic APOE3 and APOE4 mice with and without five familial AD (FAD) mutations (16 groups; n = 7-10 each). In the different brain regions, females had higher levels than males of either saturated or polyunsaturated FFAs or both. In the hippocampus of young males, but not of older males, APOE4 and FAD each induced 1.3-fold higher levels of almost all FFAs. In young and older females, FAD and to a less extent APOE4-induced shifts among saturated, monounsaturated, and polyunsaturated FFAs without affecting total FFA levels. In cortex and cerebellum, APOE4 and FAD had only minor effects on individual FFAs. The effects of APOE4 and FAD on FFA levels and FFA profiles in the three brain regions were strongly dependent of sex and age, particularly in the hippocampus. Here, most FFAs that are affected by FAD are similarly affected by APOE4. Since APOE4 and FAD affected hippocampal FFA profiles already at young age, these APOE4-induced alterations may modulate the pathogenesis of AD.
摘要：
编码载脂蛋白(Apo)E4的APOE4是阿尔茨海默病(AD)的最强遗传危险因素。ApoE是细胞间脂质运输的关键。脂肪酸对于脑完整性和认知性能是必需的,并且与神经变性有关。我们确定了AD和APOE4对脑游离脂肪酸（FFA）谱的性别和年龄依赖性作用。通过LC-MS/MS测定海马中的FFA谱,皮质,女性和男性的小脑，年轻（≤3个月）和年龄较大（>5个月），具有和不具有五个家族性AD(FAD)突变的转基因APOE3和APOE4小鼠(16组;每组n=7-10)。在不同的大脑区域，女性的饱和或多不饱和FFA水平均高于男性。在年轻男性的海马中，但不是年长的男性，APOE4和FAD各自诱导几乎所有FFA的1.3倍高的水平。在年轻和年长的女性中，FAD和较小程度的APOE4诱导的饱和，单不饱和,和多不饱和FFA，而不影响总FFA水平。在大脑皮层和小脑,APOE4和FAD对个体FFA仅有较小的影响。APOE4和FAD对三个脑区FFA水平和FFA谱的影响强烈依赖于性别和年龄,特别是在海马区。这里,受FAD影响的大多数FFA同样受APOE4影响。由于APOE4和FAD在年轻时已经影响了海马FFA谱，这些APOE4诱导的改变可能调节AD的发病机制。
