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.

Rats with Premature Birth-Type Brain Damage Show Neurologic Improvement After Stem Cell Transplants

Can stem cells transferred into the brains of newly-born babies with brain damage reverse brain damage? A study presented at the Society for Maternal-Fetal Medicine’s annual meeting in Dallas, Texas, researchers suggests that such a treatment might actually work. In this study, early transplantation of human placenta-derived mesenchymal stem cells into the lateral ventricles of neonatal rats with birth-related brain damage is feasible in this animal model. The transplanted donor cells survive and migrate within the recipient’s brain. Researchers designed this study so that the rat’s brain damage would mimic the type of brain injury observed in infants with very low birth weight.

Preterm delivery is one of the major causes of neonatal brain damage. Despite all efforts to prevent it, survivors of premature birth often suffer from some kind of injury to the brain. Survivors of preterm labor often display cognitive, behavioral, attention related and/or socialization deficits in twenty-five to fifty percent of cases; and major motor deficits in five to ten percent of cases.

Those infants with very low birth weights compose the majority of neonatal encephalopathy Such infants present with hypoxia-ischemia (low oxygen delivery to the tissues, which results in cell death and tissue damage) and inflammation. Approximately 63,000 infants are born in the United States with a very low birth weight (one to five percent of all live births). In order to understand the pathology of very premature infants, and if stem cells could ameliorate their conditions, this study, Early Intracranial Mesenchymal Stem Cell Therapy After a Perinatal Rat Brain Damage, was undertaken. This study investigated the neuroprotective effects of transplanted mesenchymal stem cells in recently born rats that had brain injuries that mimicked those found in infants with a very low birth weight.

One of the study’s authors, Martin Müller, MD, of the University of Bern, Obstetrics and Gynecology, Bern, Switzerland, said: “Stem cells are a promising source for transplant after a brain injury because they have the ability to divide throughout life and grow into any one of the body’s more than 200 cell types, which can contribute to the ability to renew and repair tissues. In our study, the donor cells survived, homed and migrated in the recipient brains and neurologic improvement was detected.”

Examination of the level of brain damaged after mesenchymal stem cell treatment indicated that stem cells exerted a neuroprotective effect on the brain. The transplanted cells survived in the brain, homed to damaged areas and migrated throughout the recipient brains. Furthermore, a combination of mesenchymal stem cells and erythropoietin (the signaling molecule made by the kidneys to signal to the bone marrow to make more red blood cells) might work even better.

While this work is still ongoing, it shows that such stem treatments are feasible and exert some positive effects.