Pandey Ravi S, Arnold Mattias, Batra Richa, Krumsiek Jan, Kotredes Kevin P, Garceau Dylan, Williams Harriet, Sasner Michael, Howell Gareth R, Kaddurah-Daouk Rima, Carter Gregory W
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032 USA.
Department of Psychiatry and Behavioral Sciences, Duke University, 905 W Main St, Durham, NC 27701, USA.
bioRxiv. 2023 Dec 22:2023.12.22.573059. doi: 10.1101/2023.12.22.573059.
Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation. METHODS: We investigated differences of 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 six months of age.
We 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.
Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of APOE4 carriers and replicating the serum metabolic imprint of the APOE4 genotype. Our work thus represents a significant step towards translating metabolic dysregulation from model organisms to human AD.
越来越多的证据表明，代谢障碍促成了早期阿尔茨海默病（AD）的发病机制及随后的痴呆症。跨物种保守的代谢途径中的信号为转化研究提供了一个有前景的切入点。方法：我们研究了早发性5XFAD和晚发性LOAD1（APOE4.Trem2*R47H）AD小鼠模型与C57BL/6J对照小鼠在6月龄时血清和脑代谢物的差异。
我们确定了几类代谢物的性别差异，如甘油磷脂、鞘脂和氨基酸。在两种小鼠模型中，脑和血清中的代谢特征均有显著差异。5XFAD小鼠脑代谢物的差异更强，而LOAD1小鼠血清中的差异更明显。
我们的几项发现与人类研究结果一致，显示APOE4携带者血清中甘油磷脂减少，并重现了APOE4基因型的血清代谢印记。因此，我们的工作朝着将代谢失调从模式生物转化到人类AD研究迈出了重要一步。
