den Hoedt Sandra, Crivelli Simone M, Leijten Frank P J, Losen Mario, Stevens Jo A A, Mané-Damas Marina, de Vries Helga E, Walter Jochen, Mirzaian Mina, Sijbrands Eric J G, Aerts Johannes M F G, Verhoeven Adrie J M, Martinez-Martinez Pilar, Mulder Monique T
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
Front Aging Neurosci. 2021 Oct 27;13:765252. doi: 10.3389/fnagi.2021.765252. eCollection 2021.
Apolipoprotein ε4 ()4 is a strong risk factor for the development of Alzheimer's disease (AD) and aberrant sphingolipid levels have been implicated in AD. We tested the hypothesis that the genotype affects brain sphingolipid levels in AD. Seven ceramides and sphingosine-1-phosphate (S1P) were quantified by LC-MSMS in hippocampus, cortex, cerebellum, and plasma of <3 months and >5 months old human and targeted replacement mice with or without the familial AD (FAD) background of both sexes (145 animals). mice had higher Cer(d18:1/24:0) levels in the cortex (1.7-fold, = 0.002) than mice. Mice with AD background showed higher levels of Cer(d18:1/24:1) in the cortex than mice without (1.4-fold, = 0.003). S1P levels were higher in all three brain regions of older mice than of young mice (1.7-1.8-fold, all ≤ 0.001). In female mice, S1P levels in hippocampus ( = -0.54 [-0.70, -0.35], < 0.001) and in cortex correlated with those in plasma ( = -0.53 [-0.71, -0.32], < 0.001). Ceramide levels were lower in the hippocampus (3.7-10.7-fold, all < 0.001), but higher in the cortex (2.3-12.8-fold, < 0.001) of female than male mice. In cerebellum and plasma, sex effects on individual ceramides depended on acyl chain length (9.5-fold lower to 11.5-fold higher, ≤ 0.001). In conclusion, sex is a stronger determinant of brain ceramide levels in mice than genotype, AD background, or age. Whether these differences impact AD neuropathology in men and women remains to be investigated.
载脂蛋白ε4（ε4）是阿尔茨海默病（AD）发病的一个重要风险因素，异常的鞘脂水平与AD有关。我们检验了ε4基因型影响AD患者脑鞘脂水平的假说。通过液相色谱-串联质谱法（LC-MSMS）对3个月以下和5个月以上的人类ε4携带者以及有或没有家族性AD（FAD）背景的两性靶向替代小鼠（共145只动物）的海马体、皮质、小脑和血浆中的7种神经酰胺和1-磷酸鞘氨醇（S1P）进行了定量分析。ε4携带者皮质中的神经酰胺（d18:1/24:0）水平比非携带者高（1.7倍，P = 0.002）。有AD背景的小鼠皮质中的神经酰胺（d18:1/24:1）水平比无AD背景的小鼠高（1.4倍，P = 0.003）。老年小鼠所有三个脑区的S1P水平均高于幼年小鼠（1.7 - 1.8倍，P均≤0.001）。在雌性小鼠中，海马体（r = -0.54 [-0.70, -0.35]，P < 0.001）和皮质中的S1P水平与血浆中的S1P水平相关（r = -0.53 [-0.71, -0.32]，P < 0.001）。雌性小鼠海马体中的神经酰胺水平低于雄性小鼠（3.7 - 10.7倍，P均< 0.001），但皮质中的神经酰胺水平高于雄性小鼠（2.3 - 12.8倍，P < 0.001）。在小脑和血浆中，性别对单个神经酰胺的影响取决于酰基链长度（低9.5倍至高11.5倍，P≤0.001）。总之，在小鼠中，性别比ε4基因型、AD背景或年龄更能决定脑内神经酰胺水平。这些差异是否会影响男性和女性的AD神经病理学仍有待研究。
