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other·preclinical research, biomedical research, neurology, immunology, geriatrics·PMC10486476

Cognitive Alterations in Old Mice Are Associated with Intestinal Barrier Dysfunction and Induced Toll-like Receptor 2 and 4 Signaling in Different Brain Regions

Cells · 10 authors, 3 centres

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TL;DR

This study compared young and old male mice to find that age-related cognitive impairment was associated with intestinal barrier dysfunction, increased blood levels of TLR2/4 ligands, and elevated TLR signaling in the hippocampus and prefrontal cortex.

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The study investigated cognitive aging in male C57BL/6 mice using 4-month-old (young) and 24-month-old (old) cohorts. Cognitive function, assessed via a Y-maze, was significantly impaired in old mice. Aged mice exhibited altered gut microbiota composition, impaired intestinal barrier function in the small intestine, and significantly higher levels of TLR2 and TLR4 ligands in portal and peripheral blood. Correspondingly, levels of TLR ligands and downstream signaling markers were elevated in the hippocampus and prefrontal cortex of old mice. The study suggests that in 'healthy' aging, cognitive impairment is associated with increased intestinal translocation of TLR ligands and altered TLR signaling in the brain. Limitations include the exclusive use of male mice and reliance on a single cognitive test, meaning causality was not established.

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other

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preclinical research

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ORIGINAL PAPER

PMC10486476

Cognitive Alterations in Old Mice Are Associated with Intestinal Barrier Dysfunction and Induced Toll-like Receptor 2 and 4 Signaling in Different Brain Regions

Cells

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ABSTRACT

Emerging evidence implicate the ‘microbiota–gut–brain axis’ in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like receptor (TLR) 2 and TLR4, in blood and different brain regions, and depending signaling cascades are paralleling aging associated alterations of cognition in healthy aging mice. Cognitive function was assessed in the Y-maze and intestinal and brain tissue and blood were collected in young (4 months old) and old (24 months old) male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and TLR4 ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function, senescence and TLR2 and TLR4 signaling. Cognitive function was significantly impaired in old mice. Also, in old mice, intestinal microbiota composition was significantly altered, while the relative abundance of Gram-negative or Gram-positive bacteria in the small and large intestines at different ages was not altered. Moreover, intestinal barrier function was impaired in small intestine of old mice, and the levels of TLR2 and TLR4 ligands were also significantly higher in both portal and peripheral blood. Furthermore, levels of TLR2 and TLR4 ligands, and downstream markers of TLR signaling were higher in the hippocampal and prefrontal cortex of old mice compared to young animals. Taken together, our results suggest that even in ‘healthy’ aging, cognitive function is impaired in mice going along with an increased intestinal translocation of TLR ligands and alterations of TLR signaling in several brain regions.

CITATION EXPORT

Annette Brandt, Franziska Kromm, Angélica Hernández-Arriaga et al.. Cognitive Alterations in Old Mice Are Associated with Intestinal Barrier Dysfunction and Induced Toll-like Receptor 2 and 4 Signaling in Different Brain Regions. Cells. (2023). https://doi.org/10.3390/cells12172153

AUTHORS

10 · 3 CENTRES

Annette Brandt, Franziska Kromm, Angélica Hernández-Arriaga, Inés Martínez Sánchez, Haktan Övül Bozkir, Raphaela Staltner, Anja Baumann, Amélia Camarinha-Silva, Rochellys Diaz Heijtz, Ina Bergheim

1Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria
2Animal Nutrition Department, Institute of Animal Science, University of Hohenheim, 70593 Stuttgart, Germany
3Department of Neuroscience, Karolinska Institute, Biomedicum, 17177 Stockholm, Sweden

EDITOR / REVIEWER

Carmela Conte