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The Aging Brain Needs REST

Researchers at the Harvard Medical School have discovered that a gene regulator called REST, which is active during fetal brain development, switches back on later in life to protect aging neurons from stresses including the toxic effects of abnormal proteins. The team  also showed that REST is lost in critical brain regions of people with Alzheimer's and mild cognitive impairment.

The study, published on March 19th in the journal Nature, offers an explanation for the longstanding mystery of why some people with the abnormal protein clumps characteristic of Alzheimer’s show few or no signs of cognitive decline .

A release from Harvard quotes lead researcher Bruce Yankner as saying "Our work raises the possibility that the abnormal protein aggregates associated with Alzheimer's and other neurodegenerative diseases may not be sufficient to cause dementia; you may also need a failure of the brain's stress response system. If true, this opens up a new area in terms of treatment possibilities for the more than 5 million Americans currently living with Alzheimer's disease."  

The release notes that the Centers for Disease Control lists Alzheimer's disease as the sixth leading cause of death in the United States and that a 2013 study by the RAND Corporation found that with an estimated annual toll of as much as $215 billion, Alzheimer's is America's most expensive disease. 

"Dementia is not an inevitable result of aging," said Yankner. "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."

The release reports that 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 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.

The finding surprised Yankner at first because until then, 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. REST was believed to wind down in the brain soon after birth. (It stays active elsewhere in the body and appears to protect against several kinds of cancer and other diseases.) When Yankner thought more about it, however, the finding began to make sense.

"When in a person's life are brain cells most vulnerable?" he asked. "The first time is during fetal development, when loss of young neurons would be devastating. The second is during aging, when you're bombarded by oxidative stress and misfolded or aggregated proteins, such as the amyloid beta and tau proteins seen in Alzheimer's disease. It makes sense that a system would come on at those two times to protect neurons, which are largely irreplaceable."

Having discovered this possible new role for REST, Yankner and colleagues went on to identify the specific genes REST regulates in aging neurons. They found that REST turns off genes that promote brain cell death and contribute to various pathological features of Alzheimer's disease, such as amyloid plaques and neurofibrillary tangles, while it turns on genes that help neurons respond to stress.

Lab dish experiments revealed that removing REST made neurons more vulnerable to the toxic effects of oxidative stress and amyloid beta. REST appeared to clear away and protect against the free radicals that result from oxidative stress.

To confirm REST's role, the scientists engineered mice that lacked REST only in their brains and watched what happened as they aged.

"The mice were okay as young adults, but as they got older, neurons in the brain started to die in the same places as in Alzheimer's: the hippocampus and the cortex," said Yankner. "This suggested that REST is essential for neurons to remain alive in the aging brain."

Yankner and colleagues further illuminated the relationship between REST and the aging brain through a combination of lab experiments and studies of brain tissue from elderly people with and without dementia.

The team showed that REST was activated in normal aging brains. The brains of people who developed mild cognitive impairment, by contrast, showed an early decline in REST. The affected brain regions of people with Alzheimer's had hardly any REST left.

"REST loss correlates very closely with memory loss, especially episodic or autobiographical memory, the type that typically declines early in Alzheimer's," said Yankner.

 The team saw the same misplacement of REST when they looked at brain tissue from people with other prevalent neurodegenerative diseases involving dementia, including frontotemporal dementia and dementia with Lewy bodies.  

"The prevention of REST from getting to the nucleus may be the earliest phase in the loss of REST function. Our laboratory models suggest that this will make neurons much more vulnerable to a variety of stresses and toxic proteins," said Yankner.