Brain Protein "Rescues" Neurons From Atrophy

April 29, 1996

DURHAM, N.C. -- Duke University Medical Center neurobiologists have protected growing brain cells from atrophying from disuse by treating them with a protein believed to be involved in helping the brain "wire" itself.

The achievement with laboratory animals, reported in the Nov. 9 issue of Nature, shows that the proteins, called neurotrophins, can foster brain cell growth, and that they might offer treatment for diseases involving gain or loss of brain cell connections. These disorders might include some forms of mental retardation, certain psychiatric conditions, epilepsy and neurodegenerative diseases such as Parkinson'" disease and amyotrophic lateral sclerosis (ALS).

The researchers are postdoctoral fellow David Riddle, Assistant Professor Donald Lo and Associate Professor Lawrence Katz, all of the medical center's department of neurobiology. Their research was supported by the National Institutes of Health and the Klingenstein and McKnight foundations.

In a separate paper in the October issue of Neuron, the scientists reported the first steps in deciphering the intercellular chemical "language" that neurotrophins use in fostering brain cell growth. Graduate student Kimberley McAllister, Lo and Katz reported finding that different regions of the brain's visual cortex sprout connections, called dendrites, in response to different neurotrophins. Understanding this chemical language is a first step in learning to manipulate the growth of brain cells, the scientists said.

Previous studies at Duke and elsewhere have shown that neurotrophins generally increase the survival and growth of brain cells, or neurons. However, it was not known whether neurotrophins were, indeed, key substances that cause the brain to "wire" itself into certain functional patterns as a result of experience. The new studies, however, show that the neurotrophins are specifically critical to the growth and interconnections of developing cells.

In the experiments reported in Nature, the Duke scientists used newborn ferrets, whose eyes had not yet opened, and thus, whose brain visual pathways had not yet fully developed. The scientists kept one eye of the infant ferrets closed, which normally results in atrophy of neurons in the brain region serving that eye, compared to the neurons serving the open eye. However, when the "closed-eye" neurons were treated with the neurotrophin NT-4, the neurons grew normally. Importantly, atrophy of the neurons was not prevented by other neurotrophins, called BDNF, NT-3 or NGF, the scientists reported. This specificity showed that NT-4 was part of a regulatory system, and not a general growth factor.

Neurobiologists believe that the brain wires itself as a result of experience -- permanently strengthening neuronal connections that are more heavily used. A central mystery, however, has been how such heavier use translates into stronger connections. The new study indicates that neurotrophins -- which are released from neurons when they are triggered to fire by their neighbors -- are the substances in strengthening preferred connections.

"Thus, we conclude that NT-4 or some similar molecule, must be the endogenous factor for which neurons are competing, and that the effects of deprivation are likely to be mediated by such a factor," Katz said.

The key to the scientists' discovery was a new technique of providing neurotrophins to brain cells that, for the first time, allows researchers to determine precisely which cells received the substance. The technique involved first coating minute fluorescent latex particles with the neurotrophins. The scientists then injected the neurotrophin-soaked beads into the ferrets' visual cortexes. The beads were taken up by the brain cells, spreading throughout each cell and revealing themselves by glowing in color under the microscope.

From their experiments, the scientists theorize that defects in the cell's neurotrophin machinery likely play a key role in many neurological disorders.

"Many kinds of failures of neurons to grow, form and maintain connections might be traced to defects in neurotrophin signaling," Katz said. "These disorders might include certain forms of mental retardation such as Down's syndrome, in which brain cells have fewer dendrites." In some cases, such as certain forms of epilepsy, pathologically high levels of activity could lead to undersirable excess growth of the wrong kinds of comnnections, said Katz.

Added Lo: "Loss of some kind of neurotrophic interaction could also be the basis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Even if these diseases do not arise specifically from such defects, neurotrophins might be useful in treating them."

In the second paper, in Neuron, McAllister, Lo and Katz explored whether different parts of the visual cortex responded particularly to specific neurotrophins. Such a differential response would help confirm that neurotrophins are not simply a general growth enhancer for neurons, but represent a sort of chemical "language" that specifically regulates how different kinds of neurons develop.

In their experiments, the scientists provided different neurotrophins -- NGF, BDNF, NT-3 or NT-4 -- to slices of infant ferret brain cortex, maintained in tissue culture. Such young brain tissue is in the process of rapidly sprouting dendrites. The scientists allowed the treated slices to grow for 36 hours, then introduced a tracer that allowed them to see in great detail the structure of the tree-like neurons in the layers of visual cortex. The scientists found that each of the different neurotrophins caused certain layers of the cortex to sprout more dendrites than others.

"The findings in these two papers show the critical role that neurotrophins play in the developing brain," Katz said. "They also open the way for promising further research that could have a profound impact on basic understanding of brain development and of learning and memory, as well as clinical treatment of neurological disorders such as epilepsy."

According to Lo and Katz, future research will aim at understanding in detail the complex machinery by which brain cells produce neurotrophins and translate the chemical signals they represent into strengthened connections.

Besides NIH support for the experiments, the Duke scientists also received critical materials for these experiments, including neurotrophins, from Regeneron Pharmaceuticals of Tarrytown, N.Y. These experiments would not have been possible, the scientists said, without this kind of interaction and collaboration between academic scientists and biotechnology companies.

Duke University

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