Bruce Yankner, a professor of genetics and neurology at Harvard Medical School and the lead author of a new study published in the journal Nature, believes that a gene regulator protein—a switch that turns genes on or off—could be tied to the development of Alzheimer's disease. This gene regulator, called REST, is active during fetal brain development and gets turned on again later in life to protect aging neurons from stresses, including the abnormal proteins that build up in the brains of people with Alzheimer's. It is low or missing in people who have Alzheimer's and mild cognitive impairment.
REST is normally active in the developing brain and then switches off, though that precise time is not well defined, according to Yankner. “We have shown that it is [also] markedly induced in neurons of the aging human brain,” he said.
In the 1990s, Yankner was the first person to show that amyloid beta—the abnormal protein that accumulates in patients with Alzheimer's—has toxic effects on the brain.
A Failed Stress Response
Yankner’s team 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. On the flip side, it activates genes that help neurons respond to stress.
This means that abnormal proteins associated with neurodegenerative diseases may not be enough to trigger dementia—a person may also have to have a failed stress-response system that does not reactivate the REST protein. Yankner said that dementia is not an inevitable part of aging; the human brain can work normally for a century or more, so a mechanism must have evolved to preserve brain function and keep brain cells alive in humans—we just don’t know what that is.
REST, Yankner believes, could be an important piece of that puzzle. Brain cells are most vulnerable during fetal development and during aging. As it ages, the body is subject to oxidative stress and misfolded proteins, such as the amyloid beta and tau proteins linked to Alzheimer's disease.
“It makes sense that a system would come on at those two times to protect neurons, which are largely irreplaceable,” he said in a statement.
Testing the Impact of REST
In lab dish experiments, the team discovered that eliminating REST made neurons more susceptible to oxidative stress and amyloid beta. REST appeared to protect against the free radicals that result from oxidative stress. They also studied mice whose brains did not contain REST, and found that their neurons started to die in the hippocampus and the cortex—the same areas of the brain that are affected in Alzheimer’s patients.
Yankner's team also showed a link between REST and the aging brain via experiments and a study of brain tissue from elderly people who did and did not have dementia. In normal aging brains, REST was activated, but people with Alzheimer’s hardly had 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,” Yankner said.
His study also showed that in Alzheimer's, REST is diverted on its path to the cell nucleus and destroyed. The researchers showed that REST boosts the expression of genes that are known to increase lifespan.
A New Perspective on Brain Diseases
Yankner's research doesn’t apply only to Alzheimer’s—other conditions are also impacted by a lack of REST.
“Two other prevalent dementing neurodegenerative diseases—frontotemporal dementia and dementia with Lewy bodies—also show loss of REST from the nucleus,” Yankner said. “We anticipate that loss of REST may predispose [a person] to many neurological conditions that arise from various causes, genetic or environmental.”
Knowing this, Yankner said it may be possible to intervene in these conditions. If REST levels remain high, a person might be able to resist the effects of Alzheimer’s and other diseases, he said. Delaying the onset of disease by just a few years could have a substantial impact.
“We are looking at the possibility of monitoring REST levels in cells outside the brain as a diagnostic tool, but this is at an early stage of investigation,” Yankner said. “The REST pathway can be activated by some drugs, but we are also interested in the possibility that lifestyle changes, such as exercise, might raise REST levels as well.”