Targeting Glucose May Spark Neurogenesis – Neuroscience News

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Summary: Neural stem cells, which create new neurons in the brain, become less active with age due to elevated glucose levels. Researchers found that by knocking out the glucose transporter gene GLUT4 in older mice, they could significantly increase the production of new neurons.

This discovery opens up potential pathways for both genetic and behavioral interventions to stimulate brain repair, including the possibility of a low-carbohydrate diet. The findings could help treat neurodegenerative diseases and aid in brain recovery after injury.

Key Facts:

  • Neural stem cells become less active with age, partly due to glucose buildup.
  • Knocking out the GLUT4 gene increased new neuron production in older mice.
  • The study suggests possible treatments through glucose control or dietary changes.

Source: Stanford

Most neurons in the human brain last a lifetime, and for good reason. Intricate, long-term information is preserved in the complex structural relationships between their synapses. To lose the neurons would be to lose that critical information — that is, to forget.

Intriguingly, some new neurons are still produced in the adult brain by a population of cells called neural stem cells. As brains age, however, they become less and less adept at making these new neurons, a trend that can have devastating neurological consequences, not just for memory, but also for degenerative brain diseases such as Alzheimer’s and Parkinson’s and for recovery from stroke or other brain injury.

The glucose transporter connection “is a hopeful finding,” Brunet said. Credit: Neuroscience News

A new Stanford Medicine study, published Oct. 2 in Nature, sheds hopeful new light on how and why neural stem cells, the cells behind the generation of new neurons in the adult brain, become less active as brains age.

The research also suggests some intriguing next steps in addressing old neural stem cell passivity — or even stimulating neurogenesis, the production on new neurons, in younger brains in need of repair — by targeting newly identified pathways that could reactivate the stem cells.

Anne Brunet, PhD, professor of genetics, and her team used CRISPR platforms, molecular tools that allow scientists to precisely edit the genetic code of living cells, to conduct a genome-wide search for genes that, when knocked out, increase the activation of neural stem cells in cultured samples from old mice, but not from young ones.

“We first found 300 genes that had this ability— which is a lot,” emphasized Brunet, the Michele and Timothy Barakett Endowed Professor. After narrowing the candidates down to 10, “one in particular caught our attention,” Brunet said.

“It was the gene for the glucose transporter known as the GLUT4 protein, suggesting that elevated glucose levels in and around old neural stem cells could be keeping those cells inactive.”

Dynamic brains

There are parts of the brain, such as the hippocampus and the olfactory bulb, where many neurons have shorter lives, where they regularly expire and may be replaced by new ones, said Tyson Ruetz, PhD, a formal post-doctoral scholar in Brunet’s lab and the lead author of the Nature paper.

“In these more dynamic parts of the brain, at least in young and healthy brains,” he said, “new neurons are constantly being born and the more transient neurons are replaced by new ones.”

Ruetz, now the scientific advisor and co-founder of ReneuBio, developed a way to test the newly identified genetic pathways in vivo, “where the results really count,” Brunet said.

Ruetz took advantage of the distance between the part of the brain where the neural stem cells are activated, the subventricular zone, and the place the new cells proliferate and migrate to, the olfactory bulb, which is many millimeters away in a mouse brain.

By knocking out the glucose transporter genes in the former, waiting several weeks, then counting the number of new neurons in the olfactory bulb, the team demonstrated that knocking out the gene indeed had an activating and proliferative effect on neural stem cells, leading to a significant increase in new neuron production in living mice.

With the top intervention, they observed over 2-fold increase in newborn neurons in old mice.

“It’s allowing us to observe three key functions of the neural stem cells,” Ruetz said. “First, we can tell they are proliferating. Second, we can see that they’re migrating to the olfactory bulb, where they’re supposed to be. And third, we can see they are forming new neurons in that site.”

The same technique could also be applied to studies of brain damage, Ruetz said. “Neural stem cells in the subventricular zone are also in the business of repairing brain tissue damage from stroke or traumatic brain injury.”

‘A hopeful finding’

The glucose transporter connection “is a hopeful finding,” Brunet said. For one, it suggests not only the possibility of designing pharmaceutical or genetic therapies to turn on new neuron growth in old or injured brains, but also the possibility of developing simpler behavioral interventions, such as a low carbohydrate diet that might adjust the amount of glucose taken up by old neural stem cells.

The researchers found other provocative pathways worthy of follow-up studies. Genes relating to primary cilia, parts of some brain cells that play a critical role in sensing and processing signals such as growth factors and neurotransmitters, also are associated with neural stem cell activation.

This finding reassured the team that their methodology was effective, partly because unrelated previous work had already discovered associations between cilia organization and neural stem cell function.

It is also exciting because the association with the new leads about glucose transmission could point toward alternative avenues of treatment that might engage both pathways, Brunet said.

“There might be interesting crosstalk between the primary cilia — and their ability to influence stem cell quiescence, metabolism and function — and what we found in terms of glucose metabolism,” she said.

“The next step,” Brunet continued, “is to look more closely at what glucose restriction, as opposed to knocking out genes for glucose transport, does in living animals.”

Funding: The work was supported by the National Institutes of Health (grants P01AG036695 and R01AG056290), the Stanford Brain Rejuvenation Project and a Larry L. Hillblom Foundation Postdoctoral Fellowship. 

About this genetics and neurogenesis research news

Author: Lisa Kim
Source: Stanford
Contact: Lisa Kim – Stanford
Image: The image is credited to Neuroscience News

Original Research: Open access.
CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells” by Anne Brunet et al. Nature


Abstract

CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing.

Several genetic interventions have been found to ameliorate old brain function, but systematic functional testing of genes in old NSCs—and more generally in old cells—has not been done.

Here we develop in vitro and in vivo high-throughput CRISPR–Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice.

Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import.

We also establish a scalable CRISPR–Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains.

Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age.

Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.

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