Oct. 22, 1999 Results Could Boost Understanding Of Alzheimer's, Other Brain Disorders
New Haven, Conn. -- Yale scientists have discovered that the growth of brain cells, which normally ends in adolescence, can be re-stimulated in mature neurons with a molecular mechanism known as Notch signaling.
Because Notch signaling also may be involved in the progression of degenerative diseases like Alzheimer's, the results published in the October 22 issue of Science could help scientists find ways to treat, or even prevent, this and other brain disorders.
"Our results not only help in our understanding of brain development, but they also have considerable implications for designing new treatments for many neurological disorders," said Pasko Rakic, M.D., the study's principal investigator.
"One of the hallmarks of Alzheimer's disease is the alteration of brain cell processes that can lead to irreversible memory loss and cognitive abilities characteristic of the disorder," Rakic said. "While we are still trying to determine what role Notch signaling plays in Alzheimer's, the results of this study could open possibilities for treating and preventing these kinds of brain disorders."
As the brain develops, neurons grow rapidly by extending neurites --dendrites and axons -- which make millions of connections from birth up until adolescence, when the connections in the cerebral cortex begin to stabilize. As stabilization occurs, long term memory is acquired, allowing people to remember things throughout their lives. This new study provides a clue to how the transition from growth to stability might occur.
"We have identified the signaling pathway involved in the switch from growth to stability, as well as the associated molecules that can turn the switch on and off," said Rakic, professor and chair of neurobiology at Yale Medical School.
The main element of the signaling pathway is the Notch receptor, which was first described in studies at Yale in the 1940s and was then cloned at Yale in the 1980s, but its role in adult brain cells has not been identified until now.
In their study, Rakic and his colleagues found a new and unexpected role for the Notch gene and related molecules. The Notch receptors are present in neurons and their specialized processes called neurites. Neurons of the cerebral cortex -- a thin sheet of gray matter on the surface of the brain --grow by extending their neurites and forming connections, both of which are accompanied by an increase in activity of the Notch signaling pathway. The Notch signaling pathway gradually inhibits the extension of neurites and keeps them stable in maturity.
By inhibiting Notch activity in mature neurons, the team was able to reverse this state of stability and re-initiate neuron growth. These findings suggest that the Notch signaling pathway prevents neurites from forming new connections in the adult cerebral cortex, and therefore plays a role in regulation of growth and stability of neural connections.
In Alzheimer's disease, a mutation of the gene presenilin is responsible for the early-onset of the disease. These new results provide a clue to how mutations in presenilin, which is known to affect Notch signaling, may contribute to alteration of neurites found in the disease.
Rakic's research team included Yale graduate student Nenad Sestan and Spyros Artavanis-Tsakonas, professor of cell biology at Harvard.
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