Cell therapies might be the key to brain repair.
UCSF scientists report that they were able to prompt a new period of “plasticity,” or capacity for change, in the neural circuitry of the visual cortex of juvenile mice. The approach, they say, might some day be used to create new periods of plasticity in the human brain that would allow for the repair of neural circuits following injury or disease.
The strategy – which involved transplanting a specific type of immature neuron from embryonic mice into the visual cortex of young mice – could be used to treat neural circuits disrupted in abnormal fetal or postnatal development, stroke, traumatic brain injury, psychiatric illness and aging.
Note the list of purposes for the cell therapy includes treatment of brain aging. I am expecting stem cell therapies for the brain to eventually restore youthful levels of learning in aged brains.
The kinase enzyme cdk5 controls how well new neurons connect to other neurons. Neural stem cells developed for brain cell therapies will need very precise adjustments so that they go and connect only where they ought to.
In a paper published in the Nov. 11 issue of PLoS Biology, the team, led by Fred H. Gage, Ph.D., professor in the Laboratory of Genetics, discovered that a protein called cdk5 is necessary for both correct elaboration of highly branched and complex antennae, known as dendrites, which are extended by neurons, and the proper migration of cells bearing those antennae.
Previously described functions of cdk5 are manifold, among them neuronal migration and dendritic pathfinding of neurons born during embryonic development. "The surprising element was that the dendrites of newborn granule cells in the adult hippocampus lacking cdk5 stretched in the wrong direction and actually formed synapses with the wrong cells," explains Gage. Synapses are the specialized contact points where dendrites receive input from the long processes, or axons, of neighboring neurons.
These findings offer extremely valuable, although unanticipated, input for investigators whose goal is to develop transplantation strategies to treat brain injuries or neurodegeneration.
Replacement neurons which are not correctly programmed to migrate and connect at the right places will likely mess up cognitive processes. Stem cell therapies for the brain will not be easy to develop.
"Our data shows that cells that fail to find their 'right spot' might actually become integrated into the brain and possibly interfere with normal information processing," says the study's lead author Sebastian Jessberger, M.D., a former postdoc in the Gage lab and now an assistant professor at the Swiss Federal Institute of Technology in Zurich, Switzerland.
Gage agrees that this is a possibility, noting that therapeutic targeting of new tissue—which would presumably be derived from stem cells—to the brain or spinal cord may demand extreme accuracy. "Our findings reflect the need for therapeutic approaches that will assure that cells used in regenerative medicine are strategically placed so that they will make appropriate rather than promiscuous connections."
Whatever the precise mechanism, the discovery of cdk5's role in guiding new neurons to their proper place improves the understanding of neurogenesis in the adult hippocampus, a process that is believed to be aberrant in cognitive aging, Alzheimer disease, and some forms of epilepsy and depression. In addition, it may suggest ways to improve prospects for neural transplantation for neurodegenerative diseases such as Parkinson disease. The clinical benefits of experimental transplants have been inconsistent and largely disappointing to date, with most transplanted neurons unable to integrate into existing brain circuits. A better understanding of what neurons need to find their way and fit into their new surroundings may increase the chances of success for this treatment.
The brain is going to be the toughest organ in the body to rejuvenate. It is extremely complex and large. It requires repair and not replacement. For many organs the growth of new young replacement organs will serve as very effective ways to upgrade and reverse the effects of accumulated damage from aging. But for the brain we need to develop therapies that fix cells and replace individual cells. That's much harder. This latest research sheds light on the signaling systems which biomedical scientists and engineers will need to manipulate in order to deliver rejuvenating cell therapies to the brain.