INTRODUCTIONIncreasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation.METHODSWe investigated differences in serum and brain metabolites between the early‐onset 5XFAD and late‐onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age.RESULTSWe identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum.DISCUSSIONSeveral of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD.Highlights This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex‐specific metabolic differences, similar to human study cohorts. The early‐onset 5XFAD mouse model primarily alters brain metabolites while the late‐onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.

中文翻译：

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代谢组学分析揭示了阿尔茨海默病小鼠模型血清和大脑代谢组中独特的性别特异性特征

简介 越来越多的证据表明，代谢障碍会导致早期阿尔茨海默病 (AD) 机制和随后的痴呆。跨物种保守的代谢途径中的信号可以促进翻译。方法我们研究了 AD 早发 5XFAD 和晚发 LOAD1 (APOE4.Trem2*R47H) 小鼠模型与 C57BL/6J 对照在 6 个月时血清和脑代谢物的差异。结果我们确定了几类代谢物的性别差异，例如甘油磷脂、鞘脂和氨基酸。在两种小鼠模型中，大脑和血清的代谢特征显着不同。 5XFAD 小鼠在脑代谢物中表现出更强的差异，而 LOAD1 小鼠在血清中表现出更明显的差异。讨论我们的一些发现与人类结果一致，显示载脂蛋白 E (apoE) ε4 携带者血清中甘油磷脂减少并复制血清代谢印记的APOEε4基因型。因此，我们的工作代表着将代谢失调从模型生物转化为人类 AD 的重要一步。 这是对与阿尔茨海默病相关的两种小鼠模型的代谢组学评估。 与人类研究队列类似，小鼠模型表现出广泛的性别特异性代谢差异。 早发型 5XFAD 小鼠模型主要改变脑代谢物，而晚发型 LOAD1 模型主要改变血清代谢物。 载脂蛋白 E (apoE) ε4 小鼠重现人类甘油磷脂特征APOE大脑和血清中都有ε4携带者。