Feed microglia

Restoring the metabolism of microglia restored cognitive abilities to aging mice

Konstantin Chapliy, N+1

The lack of access to glucose in microglial cells turned out to be a key factor leading to the loss of cognitive functions during aging. Moreover, it turned out that this process can be reversible. The researchers derived lines of mice with reduced expression of prostaglandin-E2, resulting in increased glucose levels in microglia in aging mice, and cognitive abilities were restored. The work was published in the journal Nature (Minhas et al., Restoring metabolism of myeloid cells reverses cognitive decline in aging).

One of the main and most significant symptoms of aging is considered to be a weakening of cognitive functions. The exact causes of the emergence and development of such processes are still unknown. However, it is believed that an important role in brain aging is played by pro-inflammatory factors, that is, those that ensure the mobilization of an inflammatory response. Because of them, microglia (brain cells morphologically similar to immune macrophages, whose function, however, is not fully understood) lose the ability to remove improperly folded proteins, which leads to neurodegenerative processes.

According to previous studies, microglial dysfunction during aging is associated with problems of cellular energy metabolism, manifested in impaired glycolysis and mitochondrial oxidative phosphorylation.

In order to closely study the process of degeneration of CNS macrophages, Paras S. Minhas from Stanford University and his colleagues drew attention to the inflammation-related prostaglandin-E2 signaling pathway passing through one of its receptors, EP2. It is known that the level of prostaglandin-E2 increases with aging and neurodegenerative diseases. Therefore, the researchers decided to test how prostaglandin-E2 affects microglia during aging.

First, the role of prostaglandin-E2 in the aging of brain cells was studied on human macrophages originating from monocytes. In people over 65 years of age, in contrast to young people (under 35), there was an increase in prostaglandin-E2 synthesis in these cells. Since macrophage dysfunction manifests itself in response to problems with energy metabolism, the researchers looked at changes in various energy parameters of the cell. 

A gradual increase in the dose of prostaglandin-E2 led to a decrease in the intensity of glycolysis, which was assessed by fixing the indicators of extracellular acidification by protons, a side process of glycolysis. In addition, suppression of mitochondrial respiration, calculated by the rate of oxygen consumption, was observed. It is important that when an EP2 receptor agonist was added, the same parameters increased. This indicates that prostaglandin-E2 affects cellular energy metabolism precisely through the EP2 receptor.

Further, the authors conducted experiments on a line of mice with reduced expression of the EP2 receptor in microglial cells (Cd11bCre; EP2lox/lox). It turned out that the ECAR and OCR indices in the macrophages of such mice during the aging period (20 months of age) are noticeably higher than in ordinary mice (1.5 and 2 times, respectively). The cognitive abilities of the mutant line also turned out to be better: there were no differences in the performance of spatial memory tasks between aging mice and young mice (both mutants and controls with normal EP2 expression). An experiment with EP2 antagonists led to similar results.

To clarify the mechanism and the main factors of the recovery process, the researchers drew attention to other elements of the prostaglandin-E2 signaling pathway passing through EP2. This pathway triggers the activation of a number of proteins, which ultimately leads to the synthesis of glycogen. Accordingly, the level of glycogen in mutant mice was lower than in the control. Partial knockdown of the activator of glycogen synthesis, GYS1, in human macrophages reduced the level of glycogen and improved the indicators of extracellular acidification by protons and basal respiration. Moreover, activation of the signaling pathway with the help of agonists did not change metabolic parameters, which indicates the key role of GYS1 in the regenerative reactions of macrophages during aging.

The increased intensity of glycogen synthesis during aging, according to scientists, reduces the content of glucose, which serves as fuel for cells, which negatively affects the energy metabolism of microglia. Moreover, in aging mice, only glucose (but not other energy molecules ‒ pyruvate, lactate, glutamate), labeled with the radioactive carbon isotope C13, participated in metabolism. Thus, the aging of microglial cells is associated with glucose as a source of energy for the cell, the authors conclude.

Recently, more and more researchers have been studying not only neural brain cells, but also glial cells, discovering many previously unknown functions. So, it was recently found out that microglial cells are able to regulate the activity of neurons on the principle of feedback, protecting the brain from too much excitement, which is also associated with various neurodegenerative diseases.

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