| A new study shows that a gene regulator called REST, dormant in the brains of young people, switches on in normal aging brains to protect against various stresses, including abnormal proteins associated with neurodegenerative diseases. REST is lost in critical brain regions of people with Alzheimer’s. |
R esearchers at Harvard have found evidence that Alzheimer’s disease, long known for the toxic clumps and tangles that build up in the brain, may also be caused by the failure of a natural system that protects brain cells.
The protein deposits that are characteristic of Alzheimer’s disease have turned out to be unreliable for diagnosis purposes, signalling the devastating illness might have other causes.
Studies have found the protein clumps clogging the brains of some people with no cognitive impairment.
In the study, published in the journal Nature, scientists have identified a protein called REST that flips genes on and off and naturally increases during aging.
REST, has been found to represses genes involved in Alzheimer’s disease, and its levels are reduced in key brain areas of people diagnosed with Alzheimer’s or the mild cognitive impairment that precedes dementia.
REST protected brain cells from dying in the lab when exposed to a number of stresses, including the beta amyloid protein that accumulates in the brains of Alzheimer’s patients.
“One very positive, optimistic note from this study is that it suggests that dementia can be resisted by some people, and it provides the first molecular inklings of how that might occur,” said Bruce Yankner, a professor of genetics at Harvard Medical School.
The finding highlights a different approach to understanding neurodegenerative diseases: instead of focusing on the negative changes that cause disease, researchers looked for lapses in the brain’s protective mechanisms.
"The brain is a pretty tough organ and we should strive to find out what makes it so tough and capitalize on this." |
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“Dementia is not an inevitable result of aging,” said Yankner, who is also co-director of the Paul F. Glenn Laboratories for Biological Mechanisms of Aging. “We know it’s possible for the human brain to work normally for a century or more. So a robust mechanism must have evolved to preserve brain function and keep brain cells alive in long-lived organisms like us. We just haven’t learned what that mechanism is.”
Yankner believes REST may be a key piece in the solution to that puzzle. REST first came to his attention when team member Tao Lu, HMS instructor in genetics, flagged it as the most strongly activated transcriptional regulator—a switch that turns genes on or off—in the aging human brain. The team confirmed the finding through biochemical and molecular tests and high-resolution imaging.
Yankner has done foundational work in the Alzheimer’s field, describing in the 1990s how the protein deposits that form in the brains of Alzheimer’s patients are toxic. In the intervening years, however, he has become broadly interested in what happens to the brain during aging.
It was a search for those changes that led his team to the REST protein. Yankner and colleagues used a computer program to search for genetic switches that might account for the characteristic differences in gene activity between the brains of young adults and older adults. The REST protein leaped out from the data.
Because genetic studies are not feasible in humans, the team created genetically manipulated mice that lacked the REST protein. When the researchers compared month-old mice with and without REST, they had similar numbers of neurons in key brain areas, but by the time they were eight months old, more brain cells had degenerated and been lost in mice lacking the protein than in those with it. The scientists also found that among brain cells exposed to a toxin, cells with extra REST were less likely to die.
Next, they created roundworms that lacked proteins that are analogous to REST, and found that the ones lacking the protein were less likely to survive when subjected to an herbicide that causes oxidative stress. That suggested the REST mechanism for protecting brain cells is very basic to survival, because it had been conserved in starkly different species by evolution.
The researchers then analyzed human databases, including a study that has tried to eliminate some of the natural variability in people’s environment by studying clergy who have lived similar lifestyles. Those clergy in the Religious Orders Study had detailed cognitive assessments performed and also donated their brains for study after death.
The researchers found that higher levels of REST in the prefrontal cortex—a portion of the brain involved in decision-making, planning ahead, and coordinating activities—were correlated with greater ability to remember autobiographical information and events.
In addition, REST levels were significantly higher in study participants who had signs in their brain of Alzheimer’s disease but no recorded memory issues. That, along with the laboratory tests in animals, suggested the protein was helping preserve cognitive abilities.
For years, experimental drugs aimed at the known pathological signs of Alzheimer’s disease have been largely ineffective, and Yankner thinks that perhaps this variability in people’s REST levels during aging could help explain those results. His team found that REST appears to be activated in response to stress, but further work needs to be done to understand precisely why some people have higher rest levels during aging and some do not.
Already, his group is searching for experimental drugs that can turn up REST levels, and he said one intriguing finding so far is that an approved drug, lithium, appears to activate it.
As dementia rates rise, researchers believe preventive studies such as this will be critical in finding a cure. Some estimates say the number of people living with dementia will double to nearly 70 million by 2030.
SOURCE Harvard Medical School
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