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Gene regulator may play role in Alzheimer’s and other dementias

AGE SPECIFIC: A gene regulator called REST, dormant in the brains of young people (left), switches on in normal aging brains (center) to protect against various stresses, including abnormal proteins associated with neurodegenerative diseases. REST is lost in critical brain regions of people with Alzheimer’s (right). Photo: Yankner Lab

Why do neurodegenerative diseases such as Alzheimer’s affect the elderly? Why do some people live to be over 100 with intact cognitive function while others develop dementia decades earlier? And why do others, despite having brains that exhibit pathologies associated with dementia, show few or no signs of cognitive decline?

According to recent research, an explanation for these longstanding mysteries may be found in a gene regulator called REST. Active during fetal brain development, REST switches back on later in life to protect aging neurons from various stresses, including the toxic effects of abnormal proteins. Now, work by a research team led by Bruce Yankner, an HMS professor of genetics, has shown that REST is destroyed in critical regions of the brains of people with Alzheimer’s and mild cognitive impairment. The results were published online March 19 in Nature.

“Our work raises the possibility that the abnormal protein aggregates associated with Alzheimer’s or other neurodegenerative diseases may not be sufficient to cause dementia; you may also need a failure of the brain’s stress response system,” says Yankner, who also codirects the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at HMS.

The team found that REST is the most strongly activated transcriptional regulator—a switch that turns genes on or off—in the aging human brain. Until this time, REST’s only known activity in the brain occurred prenatally, when it keeps key genes turned off until progenitor cells are ready to differentiate into functional, mature neurons. After birth, REST was known to stay active elsewhere in the body and perhaps to protect against several kinds of cancer and other diseases.

When the scientists looked at REST’s role in aging neurons, they found it turns off genes that promote brain cell death and contribute to the amyloid plaques, neurofibrillary tangles, and other pathological features of Alzheimer’s disease, and that it turns on genes that help neurons respond to stress.

The team found that high levels of REST also may act to thwart dementia, even in people whose brains, donated after death, show the characteristic pathology of the disease. The researchers also found evidence that REST may play a role in longevity.


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