Impact of background strains and diet on metabolic profile in mouse model of Alzheimer’s disease

Abstract

BackgroundGenetic background is known to significantly affect the behavioral and molecular phenotypes in mice and has been well documented over many disease areas including Alzheimer’s disease (AD). However, how different background strains and their interaction with environmental factors such as high fat diet (HFD) could have an impact on metabolic phenotypes in AD not known.MethodTo determine how genetic background, diet, sex and age contributes to the metabolic profile in AD, 2.5 months old male and females 5xFAD mice on C57BL/6J (B6) and B6D2 background were fed either normal chow diet, or 45% high‐fat diet till 6 or14 months of age and compared to their age matched non‐transgenic littermate controls. Blood plasma samples were collected and a four‐mode discovery metabolomics approach on a Q‐Exactive Orbitrap coupled to an ultra‐high‐performance liquid chromatography (UHPLC) system was used to analyze metabolic changes.ResultFollowing the quality assessment of spectral data, the dataset contained a total of 21,746 features across C18 and HILIC columns run with negative and positive ionization. After further filtering for named metabolites, removing duplicates, and a Fragment Ion Search (FISh) Score > 10, a total of 3,199 unique metabolites with high confidence MS2 fragmentation remained. Using linear regression analysis on these unique metabolites, we found that diet has a substantial impact (of all the factors tested including diet, sex, age, background strain, genotype) on plasma metabolites in both the strains with and without 5XFAD genotype, both in positive and negative mode of C18 and HILIC columns. Further on examining the interactive effects of different factors, we found a stronger interaction effect of sex by diet on metabolic phenotype. Interestingly, background strain had a moderate influence on collective metabolites irrespective of sex and age of mice.ConclusionOur initial results suggest that HFD is a major factor in defining the metabolic profile in AD mice above background strain, that could affect AD pathophysiology. We are currently looking into various classes of metabolites altered following HFD feeding and performing metabolic pathway analysis to understand the underlying disease mechanisms.