Summary: Neurons in the brain directly metabolize glucose to function normally, contrary to previous beliefs that glial cells metabolize sugar and indirectly feed neurons. The findings could provide insights into the development of new therapeutic approaches for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, in which the brain’s uptake of glucose decreases in the early stages of the diseases.
Source: Gladstone Institute
The human brain has a sweet tooth, burning nearly a quarter of the body’s sugar energy, or glucose, each day. Now, researchers from the Gladstone Institutes and UC 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 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. in the magazineCell reportsNow, we have a much better understanding of the basic fuel that makes neurons work.
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. 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.
Simple sugar
Many foods we eat are broken down into glucose, which is stored in the liver and muscles, transported throughout the body, and metabolized by cells to fuel 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 don’t metabolize sugar. Instead, they proposed that glial cells consume the majority of glucose and thus feed neurons indirectly by passing them a metabolic product of glucose called lactate. However, evidence to support this theory has been scarce due to how difficult it is for scientists to generate cultures of neurons in the lab that don’t also contain glial cells.
Nakamuras’ group solved this problem by using induced pluripotent stem cells (iPS cells) to generate pure human neurons. IPS cell technology allows scientists to transform adult cells harvested from blood or skin samples into any cell type in the body.
Then, the researchers mixed the neurons with a labeled form of glucose that they could track, even if it was broken down. This experiment revealed that the neurons themselves were able to take up glucose and transform it into smaller metabolites.
To determine exactly how neurons used metabolized glucose products, 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 major pathway by which cells typically metabolize glucose. Removing one of these proteins stopped the breakdown of glucose in isolated human neurons.
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, says Nakamura, who is also an associate professor in the UCSF Department of Neurology.
Nurture learning and memory
Nakamura’s group then turned to mice to study the importance of neuronal glucose metabolism in living animals. They engineered the animals’ neurons, but not other types of brain cells, to lack the proteins needed 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 able to metabolize glucose, but also rely on glycolysis for normal function, 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 this is the case.
Myriam M. Chaumeil, PhD, an associate professor at UCSF and corresponding co-author of the new work, has developed specialized neuroimaging approaches, based on a new technology called hyperpolarized carbon-13, that reveal the levels of certain molecular products. Imaging by her group showed how the metabolism of the mice’s brains changed when glycolysis was blocked in the neurons.
Such neuroimaging methods provide unprecedented insight into brain metabolism, says Chaumeil. The promise of metabolic imaging to inform fundamental biology and improve clinical care is immense; much remains to be explored.
The imaging results helped demonstrate that neurons metabolize glucose through glycolysis in living animals. They also showed the potential of Chaumeil’s imaging approach to study how glucose metabolism changes in humans with diseases such as Alzheimer’s and Parkinson’s.
Finally, Nakamura and his collaborators 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.
The studies we conducted laid the groundwork for a better understanding of 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.
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 the Massachusetts Institute of Technology; and Jeffrey C. Rathmell of Vanderbilt University Medical Center.
Financing: 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 CA16535,6K015 ), 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 Award Ben Barres Early Career Acceleration Award.
The summary was written with the assistance of ChatGPT AI technology
About this neuroscience research news
Author: Julia Langelier
Source: Gladstone Institute
Contact: Julie Langelier – Gladstone Institute
Image: Image is public domain
Original research: Free access.
“Neurons require glucose uptake and glycolysis in vivo” by Ken Nakamura et al. Cell reports
Abstract
Neurons require glucose uptake and glycolysis in vivo
Highlights
- Neurons take up glucose and metabolize it by glycolysis to provide TCA metabolites
- hp13C MRS shows disrupted brain energy when neuronal glucose metabolism is disrupted
- Mice require neuronal glucose uptake and glycolysis for learning and memory
- Galactose metabolism is upregulated to compensate for disrupted glucose metabolism
Summary
Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy is unclear. Using metabolomics, we demonstrate that human neurons metabolize glucose through glycolysis and can rely on glycolysis to deliver the tricarboxylic acid (TCA) cycle metabolites.
To investigate the requirement for glycolysis, we generated mice with postnatal deletion of the dominant neuronal glucose transporter (GLUT3cKO) or neuronal enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice exhibit age-dependent learning and memory deficits.
Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that PKM1cKO female mice have increased pyruvate-to-lactate conversion, whereas GLUT3cKO female mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve endings, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism.
Thus, neurons metabolize glucose through glycolysisliveand require glycolysis for normal function.
