New Study Identifies New Key Player for Dementia

Amy Taylor March 20, 2014

Decades of research into the causes of dementia have focused on the clumps and tangles of abnormal proteins that appear in the brains of people with neurodegenerative diseases. However, as to why some elderly with abnormal protein clumps show little or no signs of dementia remains to be a mystery.

Now, a team of researchers from Harvard Medical School, headed by Professor Bruce Yankner, has discovered that a gene regulator active during foetal brain development, called REST, switches back on later in life to protect aging neurons from various stresses, including the toxic effects of abnormal proteins.

They also found that REST is lost in critical brain areas of people with Alzheimer’s disease or mild cognitive impairment.

"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," Prof Yankner said.

"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,"

"Dementia is not an inevitable result of aging," the professor said. "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 play a key role in that mechanism. 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. The researchers were surprised because 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 also believed to wind down in the brain soon after birth.

"When in a person’s life are brain cells most vulnerable?" he asked. "The first time is during foetal 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."

Lab dish experiments by Yankner and colleagues 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.

Source of this article:

REST and stress resistance in ageing and Alzheimer’s disease