Cognitive impairment in old age is associated with impaired toll-like receptor 2 and 4 signaling cascade in brain but higher TLR2 and TLR4 ligands in blood

Alterations in the `gut-brain-axis´ and changes in intestinal microbiota composition are discussed to be of key importance in aging associated decline, including the development of cognitive dysfunction; however, underlying mechanisms still remain to be elucidated. Here, we aimed to investigate if alterations of intestinal barrier function and levels of pathogen-associated molecular patterns and herein especially of toll-like receptor (TLR) 2 and 4 ligands are altered in blood and different brain regions in healthy old mice and if this is associated with cognitive decline. After assessing cognitive function, intestinal and brain tissue as well as blood were collected in four and 24 months old male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and four ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function and TLR2 and 4 signaling. Cognitive function was significantly impaired in old mice, associated with a significantly altered microbiota composition but no changes in the relative abundance of Gram-negative or Gram-positive bacteria in the small and large intestine at different ages. Furthermore, intestinal barrier function was impaired in the small intestine and levels of TLR2 and TLR4 ligands were significantly higher in both portal and peripheral blood. Levels of TLR2 and TLR4 ligands were also higher in the hippocampal and prefrontal cortex of old mice compared to young animals going along with alterations of markers of TLR signaling in both brain regions. Taken together, our results suggest that in mice, even in ´healthy´ aging intestinal translocation of TLR ligands is increased, which seems to be implicative for alterations of TLR signaling in several brain regions.