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).
Newswise — SAN FRANCISCO, CA—April 18, 2023—
The human mind craves sugar and utilizes almost a quarter of the body's glucose, or energy from sugar, daily. Presently, experts at Gladstone Institutes and UC San Francisco (UCSF) have illuminated the precise process by which neurons, which transmit electric impulses throughout the brain, use and process glucose, as well as how they adjust to a lack of glucose.
Earlier, researchers had postulated that a significant portion of glucose utilized by the brain was metabolized by additional brain cells known as glia, which facilitate the functioning of neurons.
"Although we were previously aware of the brain's high glucose demands, the extent to which neurons depend on glucose and the mechanisms they use to metabolize it remained unclear," stated Ken Nakamura, MD, PhD, Associate Investigator at Gladstone and senior author of the recently published study in Cell Reports. "Our current understanding of the fundamental fuel that powers neurons has significantly improved."
Previous research has demonstrated that in the initial stages of neurodegenerative illnesses like Parkinson's and Alzheimer's, the brain's absorption of glucose is reduced. The latest discoveries could pave the way for the development of novel therapeutic interventions for these illnesses and aid in comprehending how to maintain the brain's health as it ages.
Simple Sugar
Numerous foods we consume are transformed into glucose, which is accumulated in the liver and muscles, transported throughout the body, and broken down by cells to energize the chemical processes that sustain our existence.
For a long time, researchers have deliberated over what occurs to glucose in the brain, with many proposing that neurons do not directly metabolize the sugar, but instead, glial cells consume the majority of the glucose, which is then utilized to fuel neurons indirectly by transmitting them a metabolic product of glucose called lactate. Nonetheless, there has been insufficient proof to back up this theory, partly due to the difficulty of generating neuron cultures in the laboratory without also including glial cells.
Nakamura's team overcame this difficulty by creating pure human neurons using induced pluripotent stem cells (iPS cells). IPS cell technology enables scientists to convert adult cells derived from skin or blood samples into any cell category in the body.
Subsequently, the researchers combined the neurons with a tagged form of glucose that they could follow even as it disintegrated. This experiment disclosed that neurons could absorb glucose and break it down into minor metabolites themselves.
To pinpoint the precise method that neurons were employing to utilize the products of glucose metabolism, the team used CRISPR gene editing to remove two essential proteins from the cells. One of the proteins is necessary for neurons to import glucose, and the other is required for glycolysis, the primary path by which cells usually metabolize glucose. The breakdown of glucose in the isolated human neurons ceased when either of these proteins was removed.
Nakamura, who is also an associate professor in the Department of Neurology at UCSF, stated, "This is the most unequivocal and precise evidence so far that neurons are metabolizing glucose via glycolysis and require this fuel to maintain regular energy levels."
Fueling Learning and Memory
Afterwards, Nakamura's team conducted a study using mice to explore the significance of neuronal glucose metabolism in living organisms. They genetically engineered the neurons of the mice to lack the proteins necessary for glucose import and glycolysis, but not other brain cell types. As a result, as the mice aged, they experienced severe learning and memory issues.
This indicates that neurons not only have the ability to metabolize glucose but also depend on glycolysis for regular functioning, as explained by Nakamura.
He further adds, "Interestingly, we observed differences in some of the impairments in mice with glycolysis deficiency between males and females. More investigation is necessary to fully comprehend why this occurs."
Myriam M. Chaumeil, who is also an associate professor at UCSF and co-corresponding author of the study, has been working on developing specialized neuroimaging techniques using a new technology known as hyperpolarized carbon-13. These techniques reveal the levels of specific molecular products. Her team's imaging illustrated how the brain metabolism of the mice changed when glycolysis was impeded in neurons.
Chaumeil notes, "These neuroimaging techniques offer unparalleled insights into brain metabolism. The potential of metabolic imaging to enhance basic biology and clinical care is vast, and there is still much to discover."
According to Chaumeil, "The results of the imaging not only confirmed that neurons metabolize glucose through glycolysis in living animals, but they also demonstrated the potential of our imaging technique to investigate how glucose metabolism is altered in humans with conditions such as Alzheimer's and Parkinson's disease."
Eventually, Nakamura and his colleagues investigated how neurons adjust to a situation where they cannot obtain energy through glycolysis, as is possible in some brain disorders.
The researchers discovered that neurons utilize alternative energy sources, such as galactose, when unable to obtain energy through glycolysis, as seen in certain brain disorders. However, they found that galactose was not as effective as glucose in providing energy, and could not completely substitute for the absence of glucose metabolism.
Nakamura stated, "The research we have conducted lays the foundation for improving our understanding of how changes in glucose metabolism contribute to diseases."
Nakamura’s laboratory is planning to conduct further research in collaboration with Chaumeil's team to investigate how neuronal glucose metabolism changes with neurodegenerative diseases and how therapies that target the brain's energy could enhance neuronal function.
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About the Study
The paper “Neurons Require Glucose Uptake and Glycolysis In Vivo” was published online in the journal Cell Reports on April 6, 2023.
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 Alzheimer’s 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.
About Gladstone Institutes
Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.
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