Neurogenesis is the formation of new nerve cells (neurons) in the brain, and it’s a process that begins in the embryo and lasts a lifetime. But for people with Alzheimer’s disease (AD), inflammation in the brain causes the death of new neurons. That, in turn, stops the positive impact of healthy brain cells on thinking skills and memory.
Recently, however, researchers at Massachusetts General Hospital (MGH) were able to demonstrate that inducing the formation and growth of new neurons in a part of the brain responsible for encoding memories may actually improve cognition in a brain affected with AD. The study, published in the journal Science, was done on mice, but researchers are encouraged that one day there may be applications for AD treatment or prevention in humans.
“In our study we showed that exercise is one of the best ways to turn on neurogenesis, and then, by figuring out the molecular and genetic events involved, we determined how to mimic the beneficial effects of exercise through gene therapy and pharmacological agents,” says Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Research Unit and vice-chair of the hospital’s Department of Neurology.
For many years, the accepted wisdom was that new neuron development stopped sometime in adulthood. But in recent years, researchers have found contrary evidence, and now it is widely accepted that neurogenesis continues, even into old age. In adults, neurogenesis occurs in the hippocampus, a part of the brain essential for learning and memory, as well as the striatum, a part of the brain involved with reinforcement, motivation, and other cognitive functions, as well as with motor control.
Adult neurogenesis in the hippocampus is critical to learning and memory, but how conditions such as Alzheimer’s affect this process isn’t well understood. The MGH researchers set out to stimulate neurogenesis in the brains of mice with AD.
The researchers were able to trigger neurogenesis through exercise in one group of mice and with gene therapy and drugs in another group. The gene therapy promoted the creation of neural progenitor cells, which can produce cells that become neurons. Among the Alzheimer’s mice in the drugs and gene therapy group, there was limited cognitive improvement.
However, in the exercise group, the AD mice showed significant cognitive improvement and reduced levels of beta-amyloidÑthe protein that builds up between neurons in a brain with Alzheimer’s and disrupts their function.
“Although exercise-induced adult neurogenesis improved cognition in Alzheimer’s mice by turning on neurogenesis, trying to achieve that result by using gene therapy and drugs did not help,” Dr. Tanzi explains. “That was because newly born neurons, induced by drugs and gene therapy, were not able to survive in brain regions already ravaged by Alzheimer’s pathology, particularly neuroinflammation. So we asked how neurogenesis induced by exercise differs.”
Cleaning Up the Brain
Researchers noted that among the exercise mice, the physical activity also turned on the production of brain-derived neurotrophic factor (BDNF), a protein that plays a key role in the growth and, importantly, the survival of new neurons. BDNF helps create a healthier environment for the neurons to help improve brain function. Dr. Tanzi’s group was then able to use gene therapy and drugs that stimulated BDNF production to basically mimic the effects of exercise on cognitive function.
“The lesson learned was that it is not enough just to turn on the birth of new nerve cells; you must simultaneously ‘clean up’ the neighborhood in which they are being born to make sure the new cells survive and thrive,” he says. “We will next explore whether safely promoting neurogenesis in Alzheimer’s patients will help alleviate the symptoms of the disease, and whether doing so in currently healthy individuals earlier in life can help prevent symptoms later on. We are very excited to now investigate ways of implementing our new findings to more effectively treat and prevent this terrible disease.”
It could be many years before such a treatment is viable in humans, but MGH researchers are optimistic that this study may be leading them down the right road. Gene therapy is an active and potentially promising area of research for many conditions.
“While we do not yet have the means for safely achieving the same effects in (human) patients, we determined the precise protein and gene targets for developing ways to do so in the future,” says lead author Se Hoon Choi, PhD, with MGH’s Genetics and Aging Research Unit.