New Advance May Aid Alzheimer's: Early Study Shows Protein Shares Link With Disease And Reverses Memory Deficits In Mice

October 01, 1997

WASHINGTON, D.C. October 1 - For the first time, scientists have shown through genetic studies in adult mice that depletion of the protein nerve growth factor (NGF) causes a decline in learning and memory, mimicking a major characteristic of Alzheimer1s disease. An estimated 4 million Americans are affected by the degenerative ailment.

"We also have found that NGF can bring learning and memory back to normal levels in spite of the loss of about one-third of a population of cells that are important for learning and memory," says Heidi Phillips of Genentech, Inc. in San Francisco. "The finding is intriguing and adds encouragement for therapeutic approaches for Alzheimer's disease based on the principle of increasing the function of remaining brain cells." Her study is published in the October 1 issue of The Journal of Neuroscience.

"This is an important advance and brings us one step closer to clinical relevance," says Ira Black, an expert on NGF at Robert Wood Johnson Medical School in New Jersey. "For the first time it demonstrates that memory deficits in a genetic model possibly can be treated with prolonged infusion of NGF into the brain."

In the past, researchers suspected that NGF was important for the function and survival of a population of cells that are crucial for learning and memory - basal forebrain cholinergic neurons. "These cells undergo degeneration in Alzheimer1s disease and their loss is believed to contribute to the memory loss observed in the disease," says Phillips. In previous work, scientists found that the administration of NGF to injured basal forebrain cholinergic neurons could improve cognitive function in elderly rats. "Technical difficulties have been an obstacle to determine if NGF is necessary for normal brain function," says Phillips.

Phillips and her co-workers overcame this challenge with genetic techniques. In the research, they studied mice bred to carry one dysfunctional copy and one normal copy of the NGF gene. (For each inherited characteristic, an organism has two genes, one inherited from each parent). Mice that lack both copies of the gene do not live long enough to study. The mice Phillips studied have learning and memory losses similar to Alzheimer1s. "The mice bearing one dysfunctional NGF gene have reduced levels of NGF in the brain, show a loss of about one-third of their basal forebrain cholinergic neurons, and display a mild, but significant impairment of performance in a learning and memory task," says Phillips. "The remaining basal forebrain cholinergic neurons are shrunken in size, indicating that they are not functioning optimally." These results show that NGF is critical for the development, survival and function of this cell population.

"In the second step of the study, administering NGF not only reverses the cell shrinkage, but also completely reverses the learning and memory deficits in these mice," says Phillips.

The scientists are optimistic that these findings could lead to further research that may result in ways to successfully treat Alzheimer1s disease and other memory disorders. NGF is now being studied for the treatment of diseases that involve defects in another type of neuron. These neurons, known as sensory neurons, convey pain and temperature information. Currently, NGF is in human clinical trials for the treatment of diabetic peripheral neuropathy and HIV-related neuropathy.

Phillips' co-authors were Karen Chen, Merry Nishimura, Mark Armanini, Craig Crowley, and Susan Spencer, also of Genentech, Inc. Phillips, Chen, Nishimura, and Armanini are members of the Society for Neuroscience, an organization of more than 27,000 basic scientists and clinicians who study the brain and nervous system. The Journal of Neuroscience is published by the Society for Neuroscience.

Society for Neuroscience

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