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

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.

A case for seeking sex-specific treatments in Alzheimer’s disease

“…Further transcriptomic analysis identified that the number of differentially expressed genes, particularly those related to glucose metabolism, was 3 times greater in female, compared with male AD, patients ( Park et al, 2023 ). Similar sex-specific differences have been reported in animal models of AD ( Guillot-Sestier et al, 2021 ; Strefeler et al, 2023 ). Impaired mitochondrial function is also a recognized change in the brains of AD patients ( Wang et al, 2020 ) and animal models of AD ( Fang et al, 2019 ; Demarest et al, 2020 ) and the evidence indicates that mitochondrial metabolism is particularly compromised in female APP/PS1 mice ( Demarest et al, 2020 ; O’Neill et al, 2022 ).…”

Metabolic Regulations of Smilax china L. against β-Amyloid Toxicity in Caenorhabditis elegans

“…Metabolic abnormalities have been associated with neurodegenerative diseases [ 17 ]. Alzheimer’s disease (AD) patients are accompanied by alterations in energy and lipid and amino acid metabolism [ 18 ]. Additionally, metabolites play a crucial role in cellular function, and any changes in metabolites reflect the outcome of molecular biology [ 19 ].…”