The sweet secrets of the brain: glucose metabolism is the key to neurodegenerative diseases

Brain Energy Boost Concept

Researchers from the Gladstone Institutes and the University of California, San Francisco have uncovered new details about how neurons metabolize glucose, which could lead to a better understanding of neurodegenerative diseases. Glial cells, which support the activity of neurons, were previously believed to metabolize much of the brain’s glucose. However, using induced pluripotent stem cells, the researchers found that neurons are able to take up glucose and transform it into smaller metabolites. In mice, neurons have been shown to rely on glycolysis for normal functioning. The findings could help develop new therapeutic approaches for neurodegenerative diseases such as Alzheimer’s and Parkinson’s and help understand how to maintain brain health as you age.

New details on how healthy neurons metabolize glucose have implications for understanding neurodegenerative diseases.

The human brain has a sweet tooth, burning nearly a quarter of the body’s sugar energy, or glucose, each day. Now, researchers at the Gladstone Institutes and the University of California, San Francisco (UCSF) have shed new light on exactly how neurons, the cells that send electrical signals throughout the brain, consume and metabolize glucose, as well as how these cells they adapt to glucose deficiencies.

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

We already knew that the brain requires a lot of glucose, but it wasn’t clear how much neurons themselves rely on glucose and what methods they use to break down the sugar, says Ken Nakamura, MD, PhD, research associate at Gladstone and senior author of the newly published study. April 6 in the magazine

Ken Nakamura, Yoshi Sei, and Myriam Chaumeil

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

Simple Sugar

Many foods we eat are broken down into glucose, which is stored in 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 in the brain, and many have suggested that neurons themselves dont metabolize the sugar. They instead proposed that glial cells 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 has been scantin part because of how hard it is for scientists to generate cultures of neurons in the lab that do not also contain glial cells.

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

Ken Nakamura and Myriam Chaumeil

Nakamura (left) and Chaumeil (right) collaborated to better understand what happens to glucose in the brain and showed that neurons directly metabolize sugar. Credit: Michael Short/Gladstone Institutes

Then, the researchers mixed the neurons with a labeled form of glucose that they could track, even as it was broken down. This experiment revealed that neurons themselves were capable of taking up the glucose and of processing it into smaller metabolites.

To determine exactly how neurons were using the products of metabolized glucose, the team removed two key 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 main pathway by which cells typically metabolize glucose. 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 metabolizing glucose through glycolysis and that they need this fuel to maintain normal energy levels, says Nakamura, who is also an associate professor in the Department of neurology at UCSF.

Fueling Learning and Memory

Nakamuras group next turned to mice to study the importance of neuronal glucose metabolism in living animals. They engineered the animals neurons but not other brain cell typesto lack the proteins required for glucose import and glycolysis. As a result, the mice developed severe learning and memory problems as they aged.

This suggests that neurons are not only capable of metabolizing glucose, but also rely on glycolysis for normal functioning, Nakamura explains.

Interestingly, some of the deficits we saw in mice with impaired glycolysis varied between males and females, he adds. More research is needed to understand exactly why that is.

Yoshi Sei

Yoshi Sei (center) is the first author of a new studyled by UCSFs Chaumeil (left) and Gladstones Nakamura (right)that provides the clearest evidence to date that neurons need glucose to maintain normal energy levels. Credit: Michael Short/Gladstone Institutes

Myriam M. Chaumeil, PhD,associate professor at UCSF and co-corresponding author of the new work, has been developing specialized neuroimaging approaches, based on a new technology called hyperpolarized carbon-13, that reveal the levels of certain molecular products. Her groups imaging showed how the metabolism of the mices brains changed when glycolysis was blocked in neurons.

Such neuroimaging methods provide unprecedented information on brain metabolism, says Chaumeil. The promise of metabolic imaging to inform fundamental biology and improve clinical care is immense; a lot remains to be explored.

The imaging results helped prove that neurons metabolize glucose through glycolysis in living animals. They also showed the potential of Chaumeils imaging approach for studying how glucose metabolism changes in humans with diseases like

Imaging Brain Metabolism in Living Animals

Chaumeil (center), seen here with Sei (left) and Nakamura (right), developed a specialized imaging approach that helped provide unprecedented information about brain metabolism in living animals. Credit: Michael Short/Gladstone Institutes

It turned out neurons use 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.

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

His lab is planning future studies on how neuronal glucose metabolism changes with neurodegenerative diseases in collaboration with Chaumeils team, and how energy-based therapies could target the brain to boost neuronal function.

Reference: Neurons Require Glucose Uptake and Glycolysis In Vivo by Huihui Li, Caroline Guglielmetti, Yoshitaka J. Sei, Misha Zilberter, Lydia M. Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L. Dayton, Martin Kampmann, Yadong Huang, Jeffrey C. Rathmell, Matthew Vander Heiden, Myriam M. Chaumeil and Ken Nakamura, 6 April 2023, Cell Reports.
DOI: 10.1016/j.celrep.2023.112335

The first authors are Huihui Li and Yoshitaka Sei of Gladstone and Caroline Guglielmetti of UCSF. Other authors are Misha Zilberter, Lauren Shields, Joyce Yang, Kevin Nguyen, Neal Bennett, Iris Lo, and Yadong Huang of Gladstone; Lydia M. Le Page, Brice Tiret, Xiao Gao, and Martin Kampmann of UCSF; Talya L. Dayton and Matthew Vander Heiden of Massachusetts Institute of Technology; and Jeffrey C. Rathmell of Vanderbilt University Medical Center.

The work was supported by the National Institutes of Health (RF1 AG064170, R01 AG065428, AG065428-03S1, R01 NS102156, R21 AI153749 and RR18928), National Institute on Aging (R01 AG061150, R01 AG071697, P01 AG073082, R01 CA168653, R35 CA242379, R01 DK105550), the UCSF Bakar Aging Research Institute, the Alzheimers Association, a Bright Focus Foundation Award, a Berkelhammer Award for Excellence in Neuroscience, and a Chan Zuckerberg Initiative Neurodegeneration Challenge Network Ben Barres Early Career Acceleration Award.

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