Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer's disease

Agostini, Alessandra; Yuchun, Ding; Li, Bai; Kendall, David A.; Pardon, Marie-Christine

Abstract

Systemic inflammation enhances the risk and progression of Alzheimer's disease (AD). Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin produced by the gut, is found in excess levels in AD where it associates with neurological hallmarks of pathology. Sex differences in susceptibility to inflammation and AD progression have been reported, but how this impacts on LPS responses remains under investigated. We previously reported in an APP/PS1 model of AD that systemic LPS administration rapidly altered hippocampal metabolism in males. Here, we used untargeted metabolomics to comprehensively identify hippocampal metabolic processes occurring at onset of systemic inflammation with LPS (100µg/kg, i.v.) in APP/PS1 mice, at an early pathological stage, and investigated the sexual dimorphism in this response. Four hours after LPS administration, both pro-and anti-inflammatory pathways were simultaneously recruited in the hippocampi of 4.5-month-old mice with a more pronounced anti-inflammatory component in females despite their pro-inflammatory metabolic signature in the absence of immune stimulation. LPS induced comparable behavioural sickness responses in male and female wild-type and APP/PS1 mice and comparable activation of both the serotonin and kynurenine pathways of tryptophan metabolism in their hippocampi. Males also exhibited a greater temperature response to LPS associated with a pro-inflammatory-like downregulation of pyruvate metabolism, exacerbated in APP/PS1 males, and methionine metabolism whereas females showed a greater cytokine response and anti-inflammatory-like downregulation of hippocampal methylglyoxal and methionine metabolism. Metabolic changes were not associated with morphological markers of immune cell activation suggesting that they constitute an early event in the development of LPS-induced neuroinflammation and AD exacerbation. These data suggest that the female hippocampus is more tolerant to acute systemic inflammation.

Citation

Agostini, A., Yuchun, D., Li, B., Kendall, D. A., & Pardon, M. (2020). Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer's disease. Brain, Behavior, and Immunity, 83, 87-111. https://doi.org/10.1016/j.bbi.2019.09.019

• Journal Article Type: Article
• Acceptance Date: Sep 24, 2019
• Online Publication Date: Sep 24, 2019
• Publication Date: 2020-01
• Deposit Date: Apr 30, 2019
• Publicly Available Date: Sep 30, 2019
• Print ISSN: 0889-1591
• Electronic ISSN: 1090-2139
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 83
• Pages: 87-111
• DOI: https://doi.org/10.1016/j.bbi.2019.09.019
• Keywords: Inflammation; Lipopolysaccharide; Alzheimer's disease; APP/PS1 mouse model; sex differences; hippocampus; microglia; metabolomics; serotonin; methionine Taxonomy Neuroscience; Alzheimer's Disease; Inflammation Manuscript category Neurosciences
• Public URL: https://nottingham-repository.worktribe.com/output/1881020
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0889159119303757