Restoring metabolism of myeloid cells reverses cognitive decline in ageing

 

Main ideas, conclusion, background

Maladaptive inflammation in the brain and other parts of the body causes cognitive decline and many diseases associated with aging. The main cause of this immune dysfunction is PGE2, which is a lipid messenger part of the COX-2 pathway, and it is responsible for modulating inflammation. The molecule is synthesized in monocyte-derived macrophages (MDMs) and is greatly expressed in individuals over 65 years old. PGE2 reduces glycolysis and inhibits mitochondrial oxygen consumption reducing the immune cells’ overall available energy which leads to a proinflammatory state and causes immune dysfunction. PGE2 interacts prominently with the EP2 G-protein coupled receptors which, like PGE2, is greatly expressed in older individuals. Minhas et al have discovered that inhibiting the EP2 receptor in myeloid cells prevents many diseases associated with aging and can return the cells to a more youthful state. 

Methods and results

Minhas et al discovered that by deleting the EP2 receptor on mice myeloid cells, older mice were able to perform as well as younger mice in location memory and Barnes maze tasks. By isotope tracing 13C, Minhas et al were also able to confirm that in mice with deleted EP2 receptors, glucose tended towards glycolysis for direct energy instead of glycogen synthesis for long term energy storage. Moreover, Minhas et al transfected donor MDMs with shRNA against GYS1 to determine the oxygen consumption rate and the extracellular acidification rate in myeloid cells and found out that EP2 regulates macrophage bioenergetics. 

Graphs

Figure 1. Two graphs showing the performance of young and aged mice that are either wild type (no EP2 deletion, blue) or mutant (with EP2 deletion, red). One of the tests conducted to determine the cognitive ability of mice is the Barnes maze. It demonstrates the mices’ ability to learn and remember the exit of the maze. It looks at the time spent in the exit quadrant of the maze (left graph) and the distance between the mice and the exit (right graph). As shown in the graphs, young mice with or without EP2 deletion perform the same (as EP2 does not hinder young individuals), while aged mice with the EP2 deletion perform much better than aged mice without the deletion.

Thinking outside the box

Peripheral EP2 blockage results in changes in the blood composition, which can prevent age related diseases of cerebral vascular system, and could also penetrate brain tissue to improve neural function

 

Content Writer: Dheemanth Mahesha

Reference:

Minhas PS, et. al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature. 2021 Feb;590(7844):122-128. doi: 10.1038/s41586-020-03160-0. Epub 2021 Jan 20. PMID: 33473210.

 

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