Recent
research regarding amino acid metabolism has shown that
there may be a link between obesity and Alzheimer’s disease
(AD). This work reports a metabolomics study using targeted and untargeted
mass spectrometry-based metabolomic strategies to investigate this
link. Targeted hydrophilic interaction liquid chromatography–triple
quadrupole mass spectrometry and untargeted reversed-phase liquid
chromatography-high resolution tandem mass spectrometry assays were
developed to analyze the metabolic changes that occur in AD and obesity.
APPSwe/PS1ΔE9 (APP/PSEN1) transgenic mice
(to represent familial or early-onset AD) and wild-type littermate
controls were fed either a high-fat diet (HFD, 60% kcal from lard)
or a low-fat diet (LFD, 10% kcal from lard) from 2 months of age or
a reversal diet (HFD, followed by LFD from 9.5 months). For targeted
analyses, we applied the guidelines outlined in the Clinical and Laboratory
Standards Institute (CLSI) LC–MS C62-A document and the U.S.
Food and Drug Administration (FDA) bioanalytical method validation
guidance for industry to evaluate the figures of merit of the assays.
Our targeted and untargeted metabolomics results suggest that numerous
peripheral pathways, specifically amino acid metabolism and fatty
acid metabolism, were significantly affected by AD and diet. Multiple
amino acids (including alanine, glutamic acid, leucine, isoleucine,
and phenylalanine), carnitines, and members of the fatty acid oxidation
pathway were significantly increased in APP/PSEN1 mice on HFD compared
to those on LFD. More substantial effects and changes were observed
in the APP/PSEN1 mice than in the WT mice, suggesting that they were
more sensitive to an HFD. These dysregulated peripheral pathways include
numerous amino acid pathways and fatty acid beta oxidation and suggest
that obesity combined with AD further enhances cognitive impairment,
possibly through aggravated mitochondrial dysfunction. Furthermore,
partial reversibility of many altered pathways was observed, which
highlights that diet change can mitigate the metabolic effects of
AD. The same trends in individual amino acids were observed in both
strategies, highlighting the biological validity of the results.