The human brain has a sweet tooth, burning through nearly one-quarter of the body’s sugar energy, or glucose, day by day. Now, researchers at Gladstone Institutes and UC San Francisco (UCSF) have shed recent light on exactly how neurons-; the cells that send electrical signals through the brain-; devour and metabolize glucose and the way these cells adapt to glucose shortages.

Previously, scientists had suspected that much of the glucose utilized by the brain was metabolized by other brain cells called glia, which support the activity of neurons.

“We already knew that the brain requires loads of glucose, but it surely had been unclear how much neurons themselves depend on glucose and what methods they use to interrupt the sugar down,” says Ken Nakamura, MD, Ph.D., associate investigator at Gladstone and senior writer of the brand new study published within the journal Cell Reports. “Now, we have now a significantly better understanding of the essential fuel that makes neurons run.”

Scientists from Gladstone and UCSF have make clear exactly how neurons devour and metabolize glucose, which could have implications for understanding neurodegenerative diseases. Seen listed here are Ken Nakamura (left), Yoshi Sei (center), and Myriam Chaumeil (right). Credit: Photo: Michael Short/Gladstone Institutes

Past studies have established that the brain’s glucose uptake is decreased within the early stages of neurodegenerative diseases like Alzheimer’s and Parkinson’s. The brand new findings could lead on to the invention of recent therapeutic approaches for those diseases and contribute to a greater understanding of keep the brain healthy because it ages.

Easy Sugar

Many foods we eat are broken down into glucose, which is stored within the liver and muscles, shuttled throughout the body, and metabolized by cells to power the chemical reactions that keep us alive.

Scientists have long debated what happens to glucose within the brain, and plenty of have suggested that neurons themselves don’t metabolize the sugar. They as a substitute proposed that glial cells devour many of the glucose after which fuel neurons not directly by passing them a metabolic product of glucose called lactate. Nevertheless, the evidence to support this theory has been scant-; partially due to how hard it’s for scientists to generate cultures of neurons within the lab that don’t also contain glial cells.

Nakamura’s group solved this problem using induced pluripotent stem cells (iPS cells) to generate pure human neurons. IPS cell technology allows scientists to rework adult cells collected from blood or skin samples into any cell type within the body.

Then, the researchers mixed the neurons with a labeled type of glucose that they might track whilst it was broken down. This experiment revealed that neurons were able to taking over glucose and processing it into smaller metabolites.

To find out precisely how neurons were using the products of metabolized glucose, the team removed two critical proteins from the cells using CRISPR gene editing. Certainly one of the proteins enables neurons to import glucose, and the opposite is required for glycolysis, the predominant pathway by which cells typically metabolize glucose. Removing either of those proteins stopped the breakdown of glucose within the isolated human neurons.

“That is probably the most direct and clearest evidence yet that neurons are metabolizing glucose through glycolysis and that they need this fuel to keep up normal energy levels,” says Nakamura, who can also be an associate professor within the Department of Neurology at UCSF.

Fueling Learning and Memory

Nakamura’s group next turned to mice to review the importance of neuronal glucose metabolism in living animals. They engineered the animals’ neurons-; but not other brain cell types-; to lack the proteins required for glucose import and glycolysis. Consequently, the mice developed severe learning and memory problems as they aged.

This implies that neurons will not be only able to metabolizing glucose but additionally depend on glycolysis for normal functioning, Nakamura explains.

“Interestingly, a few of the deficits we saw in mice with impaired glycolysis varied between women and men,” he adds. “More research is required to grasp exactly why that’s.”

Myriam M. Chaumeil, Ph.D., associate professor at UCSF and co-corresponding writer of the brand new work, has been developing specialized neuroimaging approaches based on a recent technology called hyperpolarized carbon-13 that reveals the degrees of certain molecular products. Her group’s imaging showed how the metabolism of the mice’s brains modified when glycolysis was blocked in neurons.

“Such neuroimaging methods provide unprecedented information on brain metabolism,” says Chaumeil. “The promise of metabolic imaging to tell fundamental biology and improve clinical care is immense; so much stays to be explored.”

The imaging results helped prove that neurons metabolize glucose through glycolysis in living animals. Additionally they showed the potential of Chaumeil’s imaging approach for studying how glucose metabolism changes in humans with diseases like Alzheimer’s and Parkinson’s.

Finally, Nakamura and his collaborators probed how neurons adapt once they will not be in a position to get energy through glycolysis-; as may be the case in certain brain diseases.

It turned out neurons use other energy sources, similar to the related sugar molecule galactose. Nevertheless, the researchers found that galactose was not as efficient a source of energy as glucose and that it couldn’t fully compensate for the lack of glucose metabolism.

“The studies we have now carried out set the stage for higher understanding how glucose metabolism changes and contributes to disease,” says Nakamura.

His lab plans future studies on how neuronal glucose metabolism changes with neurodegenerative diseases in collaboration with Chaumeil’s team and the way energy-based therapies could goal the brain to spice up neuronal function.

About Gladstone Institutes

Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to beat disease. Established in 1979, it’s positioned within the epicenter of biomedical and technological innovation within the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is finished, funds big ideas, and attracts the brightest minds.

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