Researchers have shed light on how neurons, or nerve cells, consume and metabolise glucose, as well as how these cells adapt to glucose shortages. The researchers from Gladstone Institutes and UC San Francisco (UCSF), US, said that the new findings could lead to the discovery of new therapeutic approaches for those diseases and contribute to a better understanding of how to keep the brain healthy as it ages.
“We already knew that the brain requires a lot of glucose, but it had been unclear how much neurons themselves rely on glucose and what methods they use to break the sugar down,” says Ken Nakamura, associate investigator at Gladstone and senior author of the study published in the journal Cell Reports.
Many foods we eat are broken down into glucose, which is stored in the liver and muscles, shuttled throughout the body, and metabolised by cells to power the chemical reactions that keep us alive.
Scientists had proposed that glial cells, or cells found in the tissue of the central nervous system, consume most of the glucose and then fuel neurons indirectly by passing them a metabolic product of glucose called lactate. However, the evidence to support this theory had been scant. Nakamura’s group provided more evidence in this regard by using induced pluripotent stem cells (iPS cells) to generate pure human neurons. This had been hard so far for scientists to generate cultures of neurons in the lab that do not also contain glial cells.
Then, the researchers mixed the neurons with a labelled form of glucose that they could track, even as it was broken down. This experiment proved the ability of neurons to take up the glucose themselves and process it into smaller metabolites.
Using CRISPR gene editing, the researchers removed two key proteins from the neurons to investigate how they were using metabolised glucose products. While one of them enabled neurons to import glucose, the other was required for glycolysis, the main pathway by which cells typically metabolise glucose. They found that removing either of these proteins stopped the breakdown of glucose in the isolated human neurons.
“This is the most direct and clearest evidence yet that neurons are metabolising glucose through glycolysis and that they need this fuel to maintain normal energy levels,” said Nakamura, who is also an associate professor in the Department of neurology at UCSF.
The team next engineered mice’s neurons, but not other brain cell types, to lack the proteins required for glucose import and glycolysis. The mice were found to develop severe learning and memory problems as they aged, suggesting that neurons rely on glycolysis for for normal functioning, Nakamura explains.
“Interestingly, some of the deficits we saw in mice with impaired glycolysis varied between males and females,” he added. “More research is needed to understand exactly why that is.”
The team also studied how the neurons adapted themselves in the absence of energy received through glycolysis – as might be the case in certain brain diseases. They found that neurons used other energy sources, such as the related sugar molecule galactose. However, the researchers found that galactose was not as efficient a source of energy as glucose and that it could not fully compensate for the loss of glucose metabolism.
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