Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 9;15(1):8.
doi: 10.1186/s13195-023-01162-4.

Molecular insights into sex-specific metabolic alterations in Alzheimer's mouse brain using multi-omics approach

Abigail Strefeler  1 , Maxime Jan  2 , Manfredo Quadroni  3 , Tony Teav  1 , Nadia Rosenberg  4 , Jean-Yves Chatton  4 , Nicolas Guex  2 , Hector Gallart-Ayala  5 , Julijana Ivanisevic  6
Affiliations

Molecular insights into sex-specific metabolic alterations in Alzheimer's mouse brain using multi-omics approach

Abigail Strefeler et al. Alzheimers Res Ther. .

Abstract

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by altered cellular metabolism in the brain. Several of these alterations have been found to be exacerbated in females, known to be disproportionately affected by AD. We aimed to unravel metabolic alterations in AD at the metabolic pathway level and evaluate whether they are sex-specific through integrative metabolomic, lipidomic, and proteomic analysis of mouse brain tissue.

Methods: We analyzed male and female triple-transgenic mouse whole brain tissue by untargeted mass spectrometry-based methods to obtain a molecular signature consisting of polar metabolite, complex lipid, and protein data. These data were analyzed using multi-omics factor analysis. Pathway-level alterations were identified through joint pathway enrichment analysis or by separately evaluating lipid ontology and known proteins related to lipid metabolism.

Results: Our analysis revealed significant AD-associated and in part sex-specific alterations across the molecular signature. Sex-dependent alterations were identified in GABA synthesis, arginine biosynthesis, and in alanine, aspartate, and glutamate metabolism. AD-associated alterations involving lipids were also found in the fatty acid elongation pathway and lysophospholipid metabolism, with a significant sex-specific effect for the latter.

Conclusions: Through multi-omics analysis, we report AD-associated and sex-specific metabolic alterations in the AD brain involving lysophospholipid and amino acid metabolism. These findings contribute to the characterization of the AD phenotype at the molecular level while considering the effect of sex, an overlooked yet determinant metabolic variable.

Keywords: 3xTg AD mouse; Alzheimer’s disease; Amino acids; Lipidomics; Lysophospholipids; Metabolomics; Multi-omics; Proteomics; Sex differences.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Extraction pipeline to obtain multiple data layers from the same sample. A sequential extraction method followed by an untargeted mass spectrometry approach was used to obtain multiple data layers from the same samples of whole brain homogenate (50 mg) from male and female WT and 3xTg-AD mice. A first extraction (pink arrows) was performed with methanol:water (4:1, v/v), and an aliquot of the resulting supernatant was analyzed for polar metabolites. The same sample was extracted a second time with BuMe (butanol:methanol 1:1, v/v, yellow arrows), and the pool from both organic solvent extractions was evaporated, reconstituted and analyzed for complex lipids. Proteins from the remaining pellet were extracted and digested by a modified iST method (1% Na+DCA, 30mM Tris 10 mM DTT), then analyzed (green arrows). Omics data were acquired using LC-ESI-HRMS. Using MS/MS spectral matching, 119 polar metabolites, 600 unique lipid species, and 5115 proteins were annotated with high confidence. WT: wild-type; 3xTg-AD: triple transgenic Alzheimer’s disease model; LC: liquid chromatography; ESI: electrospray ionization; HRMS: high resolution mass spectrometry; MS/MS: tandem mass spectrometry
Fig. 2
Fig. 2
Multi-omics factor analysis. A Samples plotted according to factor values from MOFA. Male and female animals are represented by the colors blue and orange, respectively. WT and 3xTg-AD animals are represented by circles and crosses, respectively. B Percent of variance explained by each omics data layer per MOFA factor. MOFA, multi-omics factor analysis; M, male; F, female; WT, wild-type; 3xTg-AD, triple transgenic Alzheimer’s disease model
Fig. 3
Fig. 3
Interaction effects in the Alanine, Aspartate, and Glutamate metabolic pathway. Selected measured metabolites (beige background) and proteins (gray background, bold title) from the alanine, aspartate, and glutamate metabolic pathway are represented by boxplots. Each line of the boxplot is a quartile of the compound abundancy per sample group (relative to the median value of male WT). Boxes are colored blue or orange with triangular or circular points for males and females, respectively. Asterisks above plots denote significant p-values for a sex:genotype interaction effect, less than 0.05 (*) or less than 0.01 (**). M, male; F, female; WT, wild-type; 3xTg-AD, triple transgenic Alzheimer’s disease model
Fig. 4
Fig. 4
Interaction effects in the Arginine biosynthesis pathway. Measured metabolites (beige background) and proteins (gray background, bold title) from the arginine biosynthesis pathway are represented by boxplots. Each line of the boxplot is a quartile of the compound abundancy per sample group (relative to the median value of male WT). Boxes are colored blue or orange with triangular or circular points for males and females, respectively. Asterisks above plots denote significant p-values for a sex:genotype interaction effect, less than 0.05 (*) or less than 0.01 (**). M, male; F, female; WT, wild-type; 3xTg-AD, triple transgenic Alzheimer’s disease model
Fig. 5
Fig. 5
Genotype effects in long-chain free fatty acids. A Heatmap of median standard scores of long-chain free fatty acid species abundance in each sample group. B Schema of free fatty acid elongation in the mitochondria. Proteins are represented by boxplots where each line of the boxplot is a quartile of the compound abundancy per sample group (relative to the median value of male WT). Boxes are colored blue or orange with triangular or circular points for males and females, respectively. Asterisks above plots denote significant p-values for a genotype effect, less than 0.05 (*), less than 0.01 (**), or less than 0.001 (***). FA, free fatty acid; M, male; F, female; WT, wild-type; 3xTg-AD, triple transgenic Alzheimer’s disease model
Fig. 6
Fig. 6
Sex-specific genotype-related differences in lysophospholipids. Heatmap of median standard scores of lysophospholipid species abundance in each sample group. Asterisks next to the plot denote significant p-values for a genotype effect, less than 0.05 (*), less than 0.01 (**), or less than 0.001 (***). LPC, lysophosphatidylcholine; O, ether linkage; P plasmalogen linkage; LPE, lysophosphatidylethanolamine; LPG, lysophosphatidylglycerol; LPI, lysophosphatidylinositol; LPS lysophosphatidylserine; M, male; F, female; WT, wild-type; 3xTg-AD, triple transgenic Alzheimer’s disease model
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Alzheimer's Association 2021 Alzheimer's Disease Facts and Figures. Alzheimer's Dement. 2021;17(3):327–406. - PubMed
    1. Alzheimer Europe . Dementia in Europe yearbook 2019: Estimating the prevalence of dementia in Europe, in Dementia in Europe yearbook, A. Europe, Editior. Alzheimer Europe; 2019.
    1. Cummings J, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37. - PMC - PubMed
    1. Budd Haeberlein S, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimer's Dis. 2022;9(2):197–210. - PubMed
    1. Swanson CJ, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021;13(1):80. - PMC - PubMed

Publication types

Substances