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New Clues to Neurological Diseases Discovered

WEDNESDAY, July 5 (HealthDay News) -- Researchers have found that genetic abnormalities in molecules that regulate neuron growth may be at the root of Down syndrome and Alzheimer's disease.

These molecules, known as neurotrophins, are taken up by neurons in sac-like carriers called endosomes and transported to the main cell body, where they take charge of neuronal development and connectivity by activating protein switches called Trk receptors.

Now, two separate reports in the July 6 issue of Neuron show that a malfunction of a single gene disrupts the transport of neurotrophins and that restoring normal levels of a Trk receptor could reverse the death of neurons.

"Neurotrophins are growth factors that maintain the health of neurons," explained Susan G. Dorsey, an assistant professor at the University of Maryland Baltimore School of Nursing and lead researcher on the first study. "The thought has always been that the problem in neurodegenerative diseases has been a lack of supply of neurotrophins."

"We argue that it's not a supply problem, but it's actually receptors on the cell surface malfunctioning," she said. "This could become a new therapeutic target."

"We found that neurons are very sensitive to the levels of neurotrophin receptors," Dorsey explained. Receptors are what neurotrophins bind to so that they can be transported into the cell to support cell survival.

In a mouse model of Down syndrome, Dorsey's team found there was an overproduction of receptors that blocked neurotrophins, which led to the death of neurons. "When we corrected that, cell survival was restored," she said.

In terms of potential therapy, the focus may need to switch from trying to supply more neurotrophin to trying "to figure out how to make the neurons more responsive to the supply of neurotrophins that exist," Dorsey said.

In the second study, Stanford University researchers looked more closely at a pathway in the brain that is critical in the development of both Down syndrome and Alzheimer's disease.

This pathway is called the cholinergic system. "Most of the treatments currently available for Alzheimer's target and attempt to make the cholinergic system more effective," said study co-author Dr. Ralph A. Nixon, a professor of psychiatry and cell biology at New York University. Nerve growth factor has been found to be essential for the survival of neurons that are part of the cholinergic system, he noted.

In the study, the researchers found that, in the same mouse model used in the previous study, there is an alteration in the mechanism that transmits the nerve growth factor signal, Nixon said. "We have not known much about why, in Alzheimer's disease, these neurons are vulnerable. This study identifies the gene that is related to the survival of neurons. So, it links a genetic cause of Alzheimer's disease to a specific biochemical mechanism."

Nerve growth factor has been tried as a treatment for Alzheimer's, Nixon said. "The trials had to be terminated due to side effects," he said. "The challenge is to find a way to deliver nerve growth factor in a way that would be effective and to control their levels so that they would have beneficial effects and not side effects."

Commenting on the first study, Nixon saw a relationship in the genetic problems affecting the normal functioning of growth factors. "Both studies show that there are two different growth factors that are impeded from functioning in the correct way," Nixon said. "It appears that problems with growth factors are really driving the destruction of neurons."

Nixon thought that either adding more growth factor to overwhelm the lack of production or to flood the receptors may be a therapy in the future. Another strategy might be to target the cell receptors, he said.

One expert thinks that these findings may open a door to new treatments for Alzheimer's disease.

"These two papers provide support for the role of growth factor abnormalities in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease," said Dr. Murray Raskind, director of the Alzheimer's Disease Research Center at the VA Puget Sound Health Care System.

"Although these have been subjects of study by Alzheimer's disease investigators for decades, it has been difficult to link these intriguing factors that protect and promote neuronal integrity to mechanisms of disease. These new findings provide impetus to this field, and have potentially important therapeutic implications," Raskind said.

More information

The Alzheimer's Association can tell you more about Alzheimer's disease.

(SOURCES: Susan G. Dorsey, Ph.D., assistant professor, University of Maryland Baltimore School of Nursing, Baltimore; Ralph A. Nixon, M.D., Ph.D., spokesman, Alzheimer's Association, and professor, psychiatry and cell biology, New York University, New York City; Murray Raskind, M.D., director, Alzheimer's Disease Research Center, Psychiatry and Behavioral Science, VA Puget Sound Health Care System, Seattle; July 6, 2006, Neuron)

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