Metabolomics profiling reveals distinct signatures in the serum and brain metabolomes in mouse models of Alzheimer’s Disease

Abstract

AbstractBackgroundProgress in development of efficacious therapies for Alzheimer’s disease (AD) is hampered due to our limited understanding of underlying pathological mechanisms. Increasing evidence suggests that metabolic impairments prior to symptom development can contribute to disease mechanisms and subsequent dementia. Signals in metabolomic pathways conserved across species could provide a promising entry point to translate experimental findings in preclinical mouse models to humans.MethodIn this study, first we systematically investigated sex‐stratified differences of serum and brain metabolites between the APOE4.Trem2*R47H and the 5XFAD mouse models of AD to C57BL/6J controls at six months of age. Metabolite levels were measured using the targeted AbsoluteIDQ®‐p180 platform (Biocrates AG, Innsbruck, Austria). Next, we did P500 panel and supplemented it with four mode discovery metabolomics for the C57BL/6J controls, APOE4.Trem2*R47H, and hAPP.APOE4.Trem2*R47H mouse models at 12 months of age.ResultWe identified strong metabolic sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Further, we identified that serum levels of glycerophospholipids were reduced in APOE4.Trem2R47H mice compared to C57BL/6J controls, while levels of these metabolites in the same animals were greater in both male and female brains of APOE4.Trem2R47H and 5XFAD mice. Several of these findings were consistent with recent results in humans, which suggested a similar decrease in the same metabolites in serum of APOE4 carriers and indicates a serum‐based effect of APOE genotype in the ADNI and ROSMAP cohorts. We simultaneously observed an increase in the same metabolites in brain, consistent across humans and mice. Further, we observed comparable results across different metabolic platforms.ConclusionOverall, metabolomic signatures were notably different between brain and serum in mouse models. The 5xFAD mice exhibited stronger effects in brain, whereas the APOE4.Trem2R47H mouse showed more pronounced effects in serum. These findings are consistent with high levels of amyloid pathology in 5xFAD mouse brains and the modifications of serum biomarkers in APOE4.Trem2R47H mice. We were able to identify patterns of metabolic changes related to human AD in our mice models. Our work thus represents a first roadmap towards translating metabolic dysregulation from model organisms to human AD.