Summary: Neurological stem cell, which create new neurons in the brain, be less effective with time due to elevated sugar levels. Scientists discovered that they could substantially increase the production of new cells by knocking out the sugar carrier protein GLUT4 in older animals.
This finding opens up possible avenues for low-carbohydrate diets as well as hereditary and behavioral interventions to promote brain repair. The findings may be used to treat neurological diseases and promote head recovery following injury.
Important Facts:
- Neurological stem cells lose activity as they get older, partially as a result of insulin accumulation.
- In older animals, knocking out the GLUT4 protein resulted in increased fresh nerve creation.
- The review makes recommendations for possible treatments that can be controlled by sugar or altered eating habits.
Origin: Stanford
Most cells in the human mind last a lifetime, and for good reason. Intricate, long-term data is preserved in the sophisticated structural interactions between their connections. Losing the cells may mean losing that crucial information, or worse, to ignore.
Unsurprisingly, a population of cells known as neural stem cells is also responsible for the generation of some fresh neurons in the adult brain. As brains age, however, they become less and less adept at making these new neurons, a pattern that can have damaging neurological consequences, not just for storage, but also for aging brain diseases such as Alzheimer’s and Parkinson’s and for healing from injury or other brain damage.
A new Stanford Medicine , investigation, published Oct. 2 in , Nature, sheds cheerful new light on how and why neural stem cells, the cells behind the generation of new neurons in the adult head, become less effective as brains time.
The study also makes some interesting suggestions for how to address older neural stem cell passivity, or even stimulate neurogenesis, the production of new neurons, in younger brains in need of repair, by focusing on recently discovered pathways that may reactivate the stem cells.
Anne Brunet, PhD, professor of genetics, and her team used CRISPR platforms, chemical tools that allow scientists to accurately alter the genetic code of living cells, to perform a genome-wide search for genes that, when knocked out, enhance the activation of neural stem cells in educated samples from old mice, but , not , from fresh 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 GLUT4 protein, which suggests that elevated glucose levels in and around old neural stem cells may 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.
He claimed that “new neurons are constantly being born and that the more transient neurons are replaced by new ones in these more dynamic parts of the brain, at least in young and healthy brains.”
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 exploited the separation between the subventricular zone of the brain and the area where the new cells proliferate and migrate, the olfactory bulb, which is located in a mouse brain many millimeters away.
The team demonstrated that knocking out the gene that controls the glucose transporter had an activating and proliferative effect on neural stem cells, leading to a significant increase in new neuron production in living mice by waiting for several weeks before counting the number of new neurons in the olfactory bulb.
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. Third, we can see that they are creating new neurons at that location.
According to Ruetz, the same method could be used in studies of brain damage. ” Neuronal stem cells in the subventricular zone are also engaged in the repair of brain tissue damage from traumatic brain injuries or strokes.”
A promising discovery
The glucose transporter connection “is a hopeful finding”, Brunet said. It also raises the possibility of developing simpler behavioral interventions, such as a low-carb diet that might change the amount of glucose that old neural stem cells take up in order to stimulate new neuron growth in old or injured brains.
The researchers found other provocative pathways worthy of follow-up studies. Neural stem cell activation is also related to genes that are related to primary cilia, which are parts of some brain cells that are crucial for sensing and processing signals like growth factors and neurotransmitters.
This finding reassured the team that their method was effective, in part because unrelated earlier studies had already shown connections between cilia organization and neural stem cell function.
Brunet said that the association with the new research on glucose transmission could point to novel treatment options that could involve both pathways.
There might be some intriguing crosstalk between the primary cilia and what we discovered in terms of glucose metabolism, and their ability to influence stem cell quiescence, metabolism, and function.
” 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 news from research in genetics and neurogenesis
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
In the adult mammalian brain, the ability of neural stem cells ( NSCs ) to transition from quiescence to proliferation is affected by age. Following injury during aging, the functional decline of NSCs results in decreased production of new neurons and defective regeneration.
Although there have been several genetic treatments that have been shown to improve old brain function, systematic functional analysis of genes in old NSCs and more generally in old cells has not been done.
In this study, we develop high-throughput CRISPR–Cas9 screening platforms in vitro and in vivo to systematically discover gene knockouts that increase NSC activation in old mice.
More than 300 gene knockouts that specifically restore the activation of old NSCs were discovered during genome-wide screens in primary cultures of young and old NSCs. The top gene knockouts play a role in glucose import and cilium organization.
We also create a scaleable CRISPR–Cas9 screening platform in vivo that identified 24 gene knockouts that promote new brain cell activation and the development of new neurons in older brains.
Notably, the knockout of , Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. NSCs increase in glucose uptake as they age, and transient glucose starvation restores the ability of older NSCs to activate. Therefore, a rise in glucose uptake may explain the NSC activation decline as a result.
Our research provides scalable platforms for systematically identifying genetic interventions that, in addition to in vivo, boost the function of old NSCs, with significant implications for preventing regenerative decline as we age.
