Thymosin beta 4 prevents systemic lipopolysaccharide-induced plaque load in middle-age APP/PS1 mice

Othman, Othman; Marshall, Hayley; Masterson, Mitchell; Winlow, Poppy; Gibson, Graham; Ding, Yuchun; Pardon, Marie-Christine

Abstract

Lipopolysaccharide (LPS) produced by the gut during systemic infections and inflammation is thought to contribute to Alzheimer's disease (AD) progression. Since thymosin beta 4 (Tβ4) effectively reduces LPS-induced inflammation in sepsis, we tested its potential to alleviate the impact of LPS in the brain of the APPswePS1dE9 mouse model of AD (APP/PS1) and wildtype (WT) mice. 12.5-month-old male APP/PS1 mice (n = 30) and their WT littermates (n = 29) were tested for baseline food burrowing performance, spatial working memory and exploratory drive in the spontaneous alternation and open-field tests, prior to being challenged with LPS (100ug/kg, i.v.) or its vehicle phosphate buffered saline (PBS). Tβ4 (5 mg/kg, i.v.) or PBS, was administered immediately following and at 2 and 4 h after the PBS or LPS challenge, and then once daily for 6 days (n = 7-8). LPS-induced sickness was assessed though monitoring of changes in body weight and behaviour over a 7-day period. Brains were collected for the determination of amyloid plaque load and reactive gliosis in the hippocampus and cortex. Treatment with Tβ4 alleviated sickness symptoms to a greater extent in APP/PS1 than in WT mice by limiting LPS-induced weight loss and inhibition of food burrowing behaviour. It prevented LPS-induced amyloid burden in APP/PS1 mice but increased astrocytic and microglial proliferation in the hippocampus of LPS-treated WT mice. These data show that Tβ4 can alleviate the adverse effects of systemic LPS in the brain by preventing exacerbation of amyloid deposition in AD mice and by inducing reactive microgliosis in aging WT mice.

Citation

Othman, O., Marshall, H., Masterson, M., Winlow, P., Gibson, G., Ding, Y., & Pardon, M.-C. (2023). Thymosin beta 4 prevents systemic lipopolysaccharide-induced plaque load in middle-age APP/PS1 mice. International Immunopharmacology, 117, Article 109951. https://doi.org/10.1016/j.intimp.2023.109951

• Journal Article Type: Article
• Acceptance Date: Feb 20, 2023
• Online Publication Date: Mar 4, 2023
• Publication Date: 2023-04
• Deposit Date: May 9, 2023
• Publicly Available Date: May 12, 2023
• Journal: International Immunopharmacology
• Print ISSN: 1567-5769
• Electronic ISSN: 1878-1705
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 117
• Article Number: 109951
• DOI: https://doi.org/10.1016/j.intimp.2023.109951
• Keywords: LPS-induced sickness, Lipopolysaccharide, Thymosin beta 4, Gliosis, Alzheimer’s disease, Amyloid load
• Public URL: https://nottingham-repository.worktribe.com/output/18805167
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1567576923002710?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Thymosin beta 4 prevents systemic lipopolysaccharide-induced plaque load in middle-age APP/PS1 mice; Journal Title: International Immunopharmacology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.intimp.2023.109951; Content Type: article; Copyright: © 2023 The Authors. Published by Elsevier B.V.