Making New Neurons When You Need Them

Western societies are aging societies, and the incidence of dementias, Alzheimer’s disease, and other diseases of the aged are on the rise. Treatments for these conditions are largely supportive, but being able to make new neurons to replace the ones that have died is almost certainly where it’s at.

At INSERM and CEA in Marseille, France, researchers have shown that chemicals that block the activity of a growth factor called TGF-beta improves the generation of new neurons in aged mice. These findings have spurred new investigations into compounds that can enable new neuron production in order to mitigate the symptoms of neurodegenerative diseases. Such treatments could also restore the cognitive abilities of those who have suffered neuron loss as a result of radiation therapy or a stroke.

The brain forms new neurons regularly to maintain our cognitive abilities, but aging or radiation therapy to treat tumors can greatly perturb this function. Radiation therapy is the adjunctive therapy of choice for brain tumors in children and adults.

Various studies suggest that the reduction in our cache of neurons contributes to cognitive decline. For example, exposure of mice to 15 Grays of radiation is accompanied by disruption to the olfactory memory and reduction in neuron production. A similar event occurs as a result of aging, but in human patients undergoing radiation treatment, cognitive decline is accelerated and seems to result from the death of neurons.

How then, can we preserve the cache of neurons in our brains? The first step is to determine the factors responsible for the decline is neuron production. In contrast to contemporary theory, neither heavy doses of radiation nor aging causes completely destruction of the neural stem cells that can replenish neurons. Even after doses of radiation and aging, neuron stem cell activity remains highly localized in the subventricular zone (a paired brain structure located in the outer walls of the lateral ventricles), but they do not work properly.

Subventricular Zone
Subventricular Zone

Experiments at the INSERM and CEA strongly suggest that in response to aging and high doses of radiation, the brain makes high levels of a signaling molecule called TGF-beta, and this signaling molecule pushes neural stem cell populations into dormancy. This dormancy also increases the susceptibility of neural stem cells into apoptosis.

Marc-Andre Mouthon, one of the main authors of this research, explained his results in this manner: “Our study concluded that although neurogenesis is reduced in aging and after a high dose of radiation, many stem cells survive for several months, retaining their ‘stem’ characteristics.”

Part two of this project showed that blocking TGFbeta with drugs restored the production of new neurons in aging or irradiated mice.

Thus targeted therapies that block TGFbeta in the brains of older patients or cancer patients who have undergone high dose radiation for a brain tumor might reduce the impact of brain lesions caused by such events in elderly patients who show distinct signs of cognitive decline.

Engineered Neural Stem Cells Restore Cognitive Function

Age-related dementia is a common problem when we age. Neurons in the brain die and neural pathways become corrupted, and we forget things and lose the ability to perform everyday tasks. Can stem cell treatments reverse cognitive decline?

Perhaps they can.  Yun-Bae Kim and Seung U. Kim from the Chungbuk National University College of Veterinary Medicine, in Cheongju, South Korea, and the Division of Neurology at the University of British Columbia Hospital, Vancouver, BC, Canada, have published a couple of papers that use neural stem cells engineered to make the neurotransmitter acetylcholine to treat rodents that have cognitive deficiencies. The results are surprising and hopeful.

Neurotransmitters are small molecules neurons release to talk to each other. Almost a century ago, physicians noticed that patients who took a drug called scopolamine failed to remember certain event after taking the drug. scopolamine is commonly used to treat motion sickness, and if any of you have ever been on board a cruise ship and experienced sea sickness, you were probably prescribed a scopolamine patch. scopolamine works by blocking the neurotransmitter acetylcholine and the fact that scopolamine takers (mind you at much higher concentrations than those used to relieve sea sickness) had memory lapses led neurologists to postulate that acetylcholine plays a role in learning and memory.


The role of acetylcholine in learning and memory has led to the development of treatments for Alzheimer’s disease patients in the form of drugs that increase the effectiveness of endogenous acetylcholine by decreasing its breakdown. These drugs, donepezil (Aricept) and rivastigmine (Exelon), are inhibitors of an enzyme called acetylcholine esterase. This enzyme degrades acetylcholine, thus effectively raising the internal levels of acetylcholine and increasing its activity. These two drugs improve the memory of patients with age-related dementia or the early stages of Alzheimer’s disease (AD).


To that end, Yun-Bae Kim and Seung U. Kim and others have engineered neural stem cells to overproduce and enzyme that synthesizes acetylcholine (choline acetyltransferase). The overproduction of this enzyme by these neural stem cells causes them to overproduce acetylcholine. Implantation of these acetylcholine-overproducing neural stem cells into the brains of laboratory animals that show cognitive declines should provide an excellent indication if such an experiment is feasible in human patients.


In their first experiment, Kim’s research team fed rats a drug that kills off neurons that use acetylcholine. When given to rodents, this drug (ethylcholine mustard aziridinium ion or AF64A) produces memory problems that have some similarities to what is observed in patients with Alzheimer’s disease. Then they transplanted human neural stem cells that made overexpressed acetylcholine into the brains of these memory-challenged rats. Remarkably, the rats with the implanted neural stem cells that overexpressed acetylcholine completely recovered their learning and memory function, and had elevated levels of acetylcholine in their cerebrospinal fluid (CSF). When the brains of these animals were examined in postmortem examinations, they discovered that the human neural stem cells had migrated to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and star-like support cells known as astrocytes. This study shows that brain transplantation of human NSCs that over-expressing acetylcholine improved the complex learning and memory problems in rats with a drug-induced type of Alzheimer’s disease.

In their second paper, the Kim research group did a very similar experiment, but they used a different drug to induce learning and memory problems (kainic acid). The drug was injected directly into the part of the brain known to play a role in learning and memory, the hippocampus. This procedure generated animals with profound learning and memory problems.

The engineered human neural stem cells were injected into the ventricles of the brain, and the cells not only found their way into the brain, but they migrated directly to the damaged area of the brain. The neural stem cells differentiated into neurons and astrocytes and restored, to some degree, the learning and memory defects in these animals.

Taken together, these experiments show that engineered neural stem cells can find their way to the damaged areas of the brain and reconstitute those damaged pathways, at least to some degree. Also, these new neural pathways restore at least some learning and memory defects that result from the death of the acetylcholine-using neurons. These experiments are crying out for more work and confirmation by other groups.

See Park D., et al., Cell Transplant. 2012;21(1):365-71 & Park D., et al., Exp Neurol. 2012; 234(2):521-6