Preprint: activating the bile acid receptor TGR5 increased the number of dividing hippocampal stem cells and improved novel-arm discrimination in aged mice

Preprint: activating the bile acid receptor TGR5 increased the number of dividing hippocampal stem cells and improved novel-arm discrimination in aged mice

A manuscript that has not yet been peer reviewed was posted on bioRxiv on October 15. Aged male mice received TC-G 1005, an experimental compound that activates TGR5, for 28 days. The researchers assessed hippocampal stem cells and performance in a Y-maze task.

Neural stem cells persist in the dentate gyrus, a region of the hippocampus. These cells can stop dividing for extended periods; this quiescent state preserves the stem cell pool. With age, quiescence deepens, and some cells show signs of stable cell cycle arrest. The authors wanted to test whether they could alter this state while preserving the stem cell pool.

TGR5 is a cell surface receptor that detects bile acid signals. The authors identified it on hippocampal stem cells and selected the activator TC-G 1005. In cell culture, the compound increased incorporation of BrdU, a marker of cell division, increased ASCL1, which is associated with exit from quiescence, and reduced p16, a marker of stable cell cycle arrest. These changes were absent when TGR5 expression was suppressed using a short RNA.

The researchers then administered TC-G 1005 to aged mice by subcutaneous injection at 5 mg per kilogram of body weight twice daily for 28 days. The dentate gyrus contained more SOX2-positive cells, representing the stem cell pool, and more cells positive for both SOX2 and BrdU, a marker of recent cell division. The p16 signal in SOX2-positive cells decreased. Treated mice explored the novel arm of the Y-maze more often; in the open-field test, they travelled the same distance as aged control mice.

The authors also tested the role of TGR5 specifically in this brain region. They injected a viral vector carrying a short RNA that suppresses TGR5 into the dentate gyrus. In mice with normal receptor levels, TC-G 1005 increased the number of dividing stem cells and improved novel-arm discrimination. In mice with suppressed TGR5 expression, the compound produced no statistically significant improvement in these measures.

The authors also compared hippocampal protein profiles in young, aged and treated aged mice. The profile in treated mice fell between those of young and aged mice; 86 proteins changed both with age and after treatment.