The human brain has a sweet tooth, burning nearly a quarter of the body’s sugar energy, or glucose, each day. Scientists have long debated what happens to glucose in the brain, and many have suggested that neurons themselves don’t metabolize sugar. Instead, they proposed that glial cells (astrocytes) consume the majority of glucose and thus feed neurons indirectly by passing them the metabolic product called lactate. However, evidence to support this theory has been scant; partly because of how difficult it is for scientists to generate cultures of neurons in the lab that don’t also contain glial cells. Previous studies have established that the brain’s uptake of glucose is decreased in the early stages of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Now, researchers at the Gladstone Institutes and the University of San Francisco have shed new light on exactly how neurons consume and metabolize glucose and how these cells adapt to its deficiencies.
The new findings could lead to the discovery of new treatment approaches for these diseases and contribute to a better understanding of how to keep the brain healthy as it ages. The research team solved this problem by using induced pluripotent stem cells to generate pure human neurons. This cell technology allows scientists to turn adult cells harvested from blood or skin samples into any type of cell in the body. Then, the researchers mixed neurons with a labeled form of glucose that they could track even as it was being broken down. This experiment revealed that neurons were able to take up glucose and transform it into smaller metabolites. To precisely determine how neurons used metabolized glucose products, the team removed two critical proteins from the cells using CRISPR gene editing. One of the proteins enables neurons to import glucose and the other is required for glycolysis, the major pathway by which cells typically metabolize glucose.
Removing one of these proteins stopped the breakdown of glucose in isolated human neurons. According to Professor Nakamura of the UCSF Department of Neurology, this is the most direct and clearest evidence that neurons are metabolizing glucose through glycolysis and that they need this fuel to maintain normal energy levels. Nakamura’s group then turned to mice to study the importance of neuronal glucose metabolism in live animals. They engineered the animals’ neurons (but not other types of brain cells) to lack the proteins needed for glucose import (GLUT) and glycolysis. As a result, the mice developed severe learning and memory problems as they aged. This suggests that neurons are not only able to metabolise glucose, but also rely on glycolysis for normal functioning, unlike previously thought. Interestingly, some of the deficits seen in mice with impaired glycolysis varied between males and females.
Myriam M. Chaumeil, PhD, an associate professor at UCSF, has developed specialized neuroimaging approaches based on a new technology called hyper-polarized carbon-13 that reveals the levels of certain molecular products. Her imaging data showed how the mice’s brain metabolism changed when glycolysis was blocked in the neurons. The imaging findings helped demonstrate that neurons metabolize glucose through glycolysis in live animals, some unprecedented insight into brain metabolism. They also showed the potential of this imaging approach to study how glucose metabolism changes in humans with diseases such as Alzheimer’s and Parkinson’s. Finally, the scientists probed how neurons adapt when they are unable to obtain energy through glycolysis, as might occur in some brain diseases. Neurons have been found to use other sources of energy, such as the related sugar molecule galactose.
However, the researchers found that galactose was not as efficient an energy source as glucose and could not fully compensate for the loss of glucose metabolism. A bit like what happens in the case of galactosemia, a genetic disease in which enzyme defects affecting galactose fail to allow the functionality of internal organs. In these syndromes, not surprisingly, there are also defects in the construction of myelin and severe mental retardation since childhood. But unlike senile dementia, the metabolic defect is only in the brain, so as there are probable glucose metabolism defects in the Alzheimer brain, there would also be defects in individuals with galactosemia albeit on a relatively distinct molecular basis. With this knowledge, scientists plan future studies on how neuronal glucose metabolism changes with neurodegenerative diseases and how energy-based therapies could condition the brain to enhance neuronal function.
- A cura del Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
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