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Protective Gene Staves Off Dementia

Activating the gene with drugs such as lithium could prevent or slow cognitive decline


The protective protein REST (green) is dormant in young adult brains (left), active in healthy older brains (center) and reduced in the brains of people with dementia (right).


SOURCE: “REST AND STRESS RESISTANCE IN AGEING AND ALZHEIMER'S DISEASE,” TAO BY LU ET AL., IN NATURE, VOL. 507; MARCH 27, 2014

More than five million people in the U.S. have Alzheimer's disease. Scientists at Harvard Medical School and their colleagues have made a breakthrough that could lead to a treatment for this currently incurable disease.

Much research on Alzheimer's has been directed at understanding the abnormally folded and entangled proteins in the brain that are key symptoms of the illness. Until now, though, scientists have been stumped to explain why many people with these anomalies do not develop the disease. A study published in March in Nature finds that a protein called REST helps the aging brain respond to stress and protects against cell death.

REST is a protein encoded by a regulator gene; it can suppress the expression of other genes. It was previously thought to be active in the brain only during fetal development, when REST oversees maturation of neural cells, becoming dormant soon after birth. Senior author Bruce Yankner, a professor of genetics and neurology at Harvard Medical School, explains that the surprising reactivation of REST in the mature brain came to his team's attention through the researchers' computer modeling of brain aging. They launched a study to better understand this protein. Through cell culture experiments, they determined that REST switches off genes that promote cell death and misfolded proteins.

Using mice, the team demonstrated that aged brains that lacked REST had much more cell death and inflammation in the hippocampus and forebrain, which is also observed in Alzheimer's. When the scientists looked at postmortem human brains, they found strong correlations between REST levels and memory function and longevity. They also observed that REST seemed to have a protective effect: the brains that had developed misfolded and tangled proteins but did not become demented had high levels of this protein.

The finding suggests exciting new possibilities for drug therapy, one of which is lithium. “Lithium very potently activates REST,” Yankner says. The drug is already a well-established therapy for bipolar disorder. The dosage has to be low, however, to avoid side effects such as tremors, vomiting and kidney failure—which are even more dangerous in the elderly. “I caution anyone against taking lithium for dementia at this time because it's experimental and potentially toxic; however, it may be a prototype for better drugs,” he says. And because REST works together with a number of other proteins, these proteins are also potential targets for treatment.

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