New research by Gladstone Institutes and UC San Francisco reveals how neurons metabolize glucose, challenging previous beliefs. Neurons can take up and process glucose themselves, relying on glycolysis for normal functioning. These findings have implications for understanding neurodegenerative diseases.
"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. Now, we have a much better understanding of the basic fuel that makes neurons run," said Ken Ph.D., Associate Investigator, Gladstone Institutes.
According to news provided by Gladstone Institutes, research by Gladstone Institutes and UC San Francisco has revealed how neurons, which use nearly a quarter of the body's glucose energy, consume and metabolize glucose, and adapt to shortages. Previous studies suggested that glial, which supports neuron activity, metabolized most of the glucose used by the brain. The associate investigator at Gladstone, Dr. Ken Nakamura, Ph.D., explained scientists already knew the brain required a lot of glucose, but it was unclear how much neurons rely on glucose and how they are able to break the sugar down. Their research has identified the process by which neurons break down glucose and how exactly the metabolized products are used.
According to the news release, glucose, obtained from the foods we eat, is stored in the liver and muscles, distributed throughout the body, and used by cells to sustain life. While scientists have debated the fate of glucose in the brain, some suggest that glial cells consume most of the glucose and supply neurons indirectly with lactate-- a metabolic product of glucose. Limited evidence to support this theory has resulted from the difficulty in cultivating glial-free neuron cultures for study. To create pure human neurons, Nakamura's group utilized induced pluripotent stem cells (iPS cells), a technology that enables the transformation of adult cells from blood or skin samples into any cell type. By mixing the neurons with labeled glucose, the team discovered that neurons could uptake glucose and process it into smaller metabolites. They also used CRISPR gene editing to remove two essential proteins, which revealed that glucose breakdown ceased in the isolated neurons without them. "This is the most direct and clearest evidence yet that neurons are metabolizing glucose through glycolysis and that they need this fuel to maintain normal energy levels," Dr. Nakamura says.
According to the news release, the team's findings may have significant implications for understanding neurodegenerative diseases. Nakamura's team turned to mice to study the importance of neuronal glucose metabolism in living animals. The team found that mice whose neurons had been engineered to lack the proteins required for glucose import and glycolysis developed severe learning and memory problems as they aged. Such results suggest that neurons are not only capable of metabolizing glucose, but they also rely on glycolysis for normal functioning. Results of the study also showed some of the deficits varied between male and female mice, but more research is needed to understand why that is.
Myriam M. Chaumeil, Ph.D., co-corresponding author of the study and an associate professor at UCSF, has been developing specialized neuroimaging approaches based on hyperpolarized carbon-13, which can detect certain molecular products. Her imaging showed how the metabolism of mice brains changed when glycolysis was blocked in neurons. According to Chaumeil, these methods provide unprecedented information on brain metabolism and have immense potential for informing fundamental biology and clinical care. The imaging results demonstrated that neurons use glycolysis to metabolize glucose in living animals and showed the potential of Chaumeil's approach for studying glucose metabolism changes in human diseases like Alzheimer's and Parkinson's. Additionally, the researchers discovered that neurons use other energy sources, such as galactose, when glucose metabolism is disrupted in certain brain diseases. However, galactose is not as efficient as glucose and cannot fully compensate for its loss. Nakamura's lab plans to collaborate with Chaumeil's team to study how neuronal glucose metabolism changes in neurodegenerative diseases and how energy-based therapies could boost neuronal function.