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Resilient neurons. High levels of REST help neurons survive into old age.

Resilient neurons. High levels of REST help neurons survive into old age.


Stressed-Out Brain Cells May Protect Against Alzheimer's

Want to live a long, dementia-free life? Stress your cells out. That’s the conclusion of a new study, which finds that heightened cellular stress causes brain cells to produce a protein that staves off Alzheimer’s disease and other forms of dementia. The work could lead to new ways to diagnose or treat such diseases.

“This paper is very impressive,” says neuroscientist Li-Huei Tsai of the Massachusetts Institute of Technology in Cambridge, who was not involved in the new work. “It puts a finger on a particular pathway that can provide some explanation as to why some people are more susceptible to Alzheimer’s.”

Alzheimer’s disease, characterized by a progressive loss of memory and cognition, affects an estimated 44.4 million people worldwide, mostly over the age of 65. The illness has been linked to the accumulation of certain proteins in the brain, but what causes symptoms has been unclear. That’s because the brains of some elderly people without dementia have the same clumps of so-called amyloid β and τ proteins typically associated with Alzheimer’s.

The new study deals with a protein called repressor element 1-silencing transcription factor (REST), which turns genes and off. Scientists knew that REST played a key role in fetal brain development by controlling the activity of certain genes, but they thought it was absent in adult brains. However, when Bruce Yankner, a neurologist at Harvard Medical School in Boston, looked at all the genes and proteins that change in brains as people age, he found that REST levels begin increasing again when a person hits their 30s. Stumped as to why, he and his colleagues isolated human and mouse brain cells and probed what factors altered REST levels and what consequences those levels had.

Any form of cellular stress, Yankner discovered, ranging from immune reactions to protein accumulation, causes an increase in REST in the brain. Such stressors become more prevalent as someone ages, Yankner says. And when REST levels rise, he found, the protein begins turning off genes involved in cell death—keeping brain cells alive even if they would normally undergo cellular suicide. While cells elsewhere can replace themselves after such cell death, most brain cells can’t. So keeping brain cells alive even through cellular stress is key to a long-lasting brain, Yankner says.

“By and large, the neurons in your brain that you’re born with are the ones you die with. So there’s a premium on keeping neurons alive, even if they’re slightly damaged,” he says. “We think REST is part of this robust machine that enables the brain to survive for a lifetime.”

When Yankner’s group measured REST levels in the autopsied brains of elderly people who had died of Alzheimer’s, levels of the protein were three times lower than in the brains of people of the same age without dementia, the team reports online today in Nature. This suggests that the protection provided by REST against brain cell death is lessened in those affected by dementia, Yankner says.

Indeed, in mice lacking REST proteins in their brains, neurons died quickly as the mice aged, but adding REST back to mice’s cells stopped the neuronal death, Yankner’s group found. Likewise, in the worm Caenorhabditis elegans, animals that lacked a worm version of REST and were also prone to accumulating amyloid β proteins showed faster neuron degeneration than worms with similar amyloid β levels but high levels of REST.

“This doesn’t dispute the idea that amyloid or τ accumulation is playing a role in Alzheimer’s,” Yankner explains. “It basically says that there are toxic influences on the brain and there are protective influences.” REST, he says, appears to be a protective influence.

“Now, this becomes a chicken-and-egg question,” Tsai says. “What causes low levels of REST and what can people do to increase them?” For the finding to have clinical implications, she says, researchers must develop ways to test REST levels in the bloodstream, rather than just in autopsied brain tissue.

Yankner says he and his colleagues are working on developing such tests, as well as sorting out whether diseases and dementias other than Alzheimer’s are linked to low REST levels. Already, they’ve shown that certain existing drugs may boost REST. “It’s an eminently druggable target,” he says. “And it’s exciting to have a new idea in a field that’s been ruled by a fairly stereotypical paradigm until now.”