Formerly, it was thought that glial cells, which support neuron activity, metabolized much of the brains glucose. They instead proposed that glial cells consume many of the glucose and then fuel nerve cells indirectly by passing them a metabolic item of glucose called lactate. To figure out exactly how nerve cells were utilizing the products of metabolized glucose, the team eliminated 2 essential proteins from the cells utilizing CRISPR gene modifying. One of the proteins allows neurons to import glucose, and the other is required for glycolysis, the primary path by which cells typically metabolize glucose. They crafted the animals neurons– but not other brain cell types– to do not have the proteins required for glucose import and glycolysis.
” We currently understood that the brain needs a great deal of glucose, but it had been unclear how much neurons themselves rely on glucose and what approaches they use to break the sugar down,” states Ken Nakamura, MD, PhD, associate private investigator at Gladstone and senior author of the brand-new research study published on April 6 in the journal Cell Reports. ” Now, we have a better understanding of the standard fuel that makes neurons run.”
Past studies have developed that the brains uptake of glucose is decreased in the early stages of neurodegenerative diseases like Alzheimers and Parkinsons. The new findings could cause the discovery of new therapeutic techniques for those illness and contribute to a much better understanding of how to keep the brain healthy as it ages.
Scientists from Gladstone and UCSF have clarified precisely how neurons take in and metabolize glucose, which might have implications for comprehending neurodegenerative diseases. Seen here are Ken Nakamura (left), Yoshi Sei (center), and Myriam Chaumeil (best). Credit: Michael Short/Gladstone Institutes
Easy Sugar
Numerous foods we consume are broken down into glucose, which is stored in the liver and muscles, shuttled throughout the body, and metabolized by cells to power the chain reaction that keep us alive.
Scientists have actually long discussed what happens to glucose in the brain, and lots of have recommended that neurons themselves dont metabolize the sugar. They instead proposed that glial cells consume many of the glucose and then fuel nerve cells indirectly by passing them a metabolic product of glucose called lactate. Nevertheless, the proof to support this theory has actually been scant– in part because of how tough it is for researchers to create cultures of neurons in the lab that do not also contain glial cells.
Nakamuras group solved this issue using caused pluripotent stem cells (iPS cells) to produce pure human nerve cells. IPS cell innovation allows scientists to change adult cells collected from blood or skin samples into any cell type in the body.
Nakamura (left) and Chaumeil (right) collaborated to better comprehend what occurs to glucose in the brain and showed that nerve cells directly metabolize sugar. Credit: Michael Short/Gladstone Institutes
Then, the scientists mixed the nerve cells with a labeled type of glucose that they could track, even as it was broken down. This experiment revealed that neurons themselves can using up the glucose and of processing it into smaller metabolites.
To identify exactly how nerve cells were utilizing the products of metabolized glucose, the team eliminated two crucial proteins from the cells using CRISPR gene editing. One of the proteins allows nerve cells to import glucose, and the other is needed for glycolysis, the primary path by which cells typically metabolize glucose. Getting rid of either of these proteins stopped the breakdown of glucose in the isolated human nerve cells.
” This is the most direct and clearest proof yet that nerve cells are metabolizing glucose through glycolysis and that they require this fuel to maintain typical energy levels,” says Nakamura, who is likewise an associate teacher in the Department of neurology at UCSF.
Fueling Learning and Memory
Nakamuras group next relied on mice to study the significance of neuronal glucose metabolic process in living animals. They engineered the animals nerve cells– however not other brain cell types– to do not have the proteins needed for glucose import and glycolysis. As an outcome, the mice established severe learning and memory issues as they aged.
This suggests that neurons are not only efficient in metabolizing glucose, however also rely on glycolysis for normal performance, Nakamura explains.
” Interestingly, some of the deficits we saw in mice with impaired glycolysis varied in between males and females,” he includes. “More research is needed to understand exactly why that is.”
Yoshi Sei (center) is the very first author of a new study– led by UCSFs Chaumeil (left) and Gladstones Nakamura (right)– that offers the clearest proof to date that neurons need glucose to maintain regular energy levels. Credit: Michael Short/Gladstone Institutes
Myriam M. Chaumeil, PhD, associate teacher at UCSF and co-corresponding author of the brand-new work, has been developing specialized neuroimaging techniques, based on a new innovation called hyperpolarized carbon-13, that reveal the levels of specific molecular products. Her groups imaging demonstrated how the metabolic process of the mices brains altered when glycolysis was obstructed in nerve cells.
” Such neuroimaging approaches provide extraordinary information on brain metabolic process,” says Chaumeil. “The pledge of metabolic imaging to inform fundamental biology and enhance clinical care is enormous; a lot stays to be explored.”
The imaging results assisted prove that neurons metabolize glucose through glycolysis in living animals. They also revealed the potential of Chaumeils imaging method for studying how glucose metabolism changes in humans with illness like Alzheimers and Parkinsons.
Nakamura and his partners penetrated how nerve cells adjust when they are not able to get energy through glycolysis– as might be the case in certain brain diseases.
Chaumeil (center), seen here with Sei (left) and Nakamura (right), established a specialized imaging approach that helped offer extraordinary information about brain metabolic process in living animals. Credit: Michael Short/Gladstone Institutes
It turned out nerve cells use other energy sources, such as the associated sugar particle galactose. However, the scientists discovered that galactose was not as effective a source of energy as glucose which it could not fully compensate for the loss of glucose metabolic process.
” The studies we have performed set the phase for better understanding how glucose metabolic process changes and adds to illness,” says Nakamura.
His lab is planning future research studies on how neuronal glucose metabolic process modifications with neurodegenerative illness in partnership with Chaumeils group, and how energy-based treatments could target the brain to enhance neuronal function.
Recommendation: “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 very 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.
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.
Researchers at Gladstone Institutes and University of California, San Francisco have found brand-new information on how neurons metabolize glucose, which could lead to a better understanding of neurodegenerative illness. Previously, it was thought that glial cells, which support neuron activity, metabolized much of the brains glucose. However, by utilizing caused pluripotent stem cells, the scientists found that neurons are capable of taking up glucose and processing it into smaller metabolites. In mice, nerve cells were revealed to rely on glycolysis for typical performance. The findings could contribute to the development of brand-new restorative methods for neurodegenerative diseases like Alzheimers and Parkinsons and assist comprehend how to preserve brain health as it ages.
New details on how healthy neurons metabolize glucose have implications for comprehending neurodegenerative illness.
The human brain has a craving for sweets, burning through nearly one quarter of the bodys sugar energy, or glucose, each day. Now, researchers at Gladstone Institutes and University of California, San Francisco (UCSF) have shed new light on precisely how nerve cells– the cells that send out electrical signals through the brain– metabolize and take in glucose, as well as how these cells adjust to glucose shortages.
Formerly, scientists had actually thought that much of the glucose utilized by the brain was metabolized by other brain cells called glia, which support the activity of nerve cells.