Fetal-Brain Protein Sparks in Old Age to Fight Dementia

Scientists have discovered that a gene-regulating protein that protects the developing brain of a fetus resurfaces in old age and may stave off dementia, a finding that could open a new path in Alzheimer’s research.

The research by Harvard University scientists published yesterday in the journal Nature, showed the protein, dubbed REST, is depleted in brains of people with Alzheimer’s. It was found at a level three times higher in those who didn’t become demented even when they had brain markings of the disease. Until now, REST wasn’t known to have a role in the adult brain.

Experimental drugs to reduce proteins such as amyloid or tau that form the hallmark brain clumps of Alzheimer’s have failed to stem cognitive decline. The finding adds support to the idea that targeting those proteins isn’t enough fight the disease. It also may explain why some people develop dementia as they age while others live long lives, lucid into their 90s or 100s, said Bruce Yankner, the study’s lead researcher.

“There’s a longstanding puzzle in neurology why a large percentage of the aging population when they die have enough abnormalities in the brain to classify as Alzheimer’s,” though they don’t develop the dementia, said Yankner, a professor of genetics at Harvard Medical School in Boston. “In addition to trying to remove toxic proteins, which many clinical trials do with limited success, we may need to augment the brain’s natural defense.”

Until now, the REST protein was thought to be active only in fetal development and switched off in the brain after birth. A series of experiments by Yankner’s team found that the protein suppresses genes involved in cell death and Alzheimer’s progression, while turning on those that protect neurons from stress.

Approaches Needed

More than 5 million Americans have Alzheimer’s disease, the most common type of dementia, a number projected to triple by 2050, according to the Alzheimer’s Association. The disease is the sixth-leading cause of death in the U.S., according to the Centers for Disease Control and Prevention. A March 6 study published in Neurology found the disease may be under-reported as a reason for a person’s death and could be the third-leading cause of mortality.

Experimental treatments, including drugs from Pfizer Inc., Johnson & Johnson and Eli Lilly & Co. that have focused on reducing amyloid haven’t slowed the debilitating loss of mental functioning that characterizes Alzheimer’s. Since 1998, there have been more than 100 attempts to develop an Alzheimer’s drug and all failed.

Protective Pathways

The discovery of REST’s potential role in the aging brain highlights the need for pursuing new directions in Alzheimer’s research, said Maria Carrillo, vice president for medical and scientific relations at the Chicago-based Alzheimer’s Association. The idea that the brain may harbor pathways, such as REST, to protect against cognitive decline is one of them. Still, any potential drug based on the today’s findings is years away.

“Its’ a fascinating take on the concept that’s been around,” she said. “There’s not as much research in the neuroprotective aspects of aging. That is the most interesting aspect of this study and it’s important to pursue and continue research in this area.”

The Alzheimer’s Association is a sponsor of a clinical trial, called LEARN, designed to look at individual variation in disease progression. One objective of LEARN is to find causes of cognitive decline besides amyloid buildup.

Study Data

In the Harvard brain-tissue tests, researchers found that the protein, mildly detectable in early adulthood, “lit up like stars,” in samples from those in their 70s to 80s, Yankner said. The study measured REST in brain samples from adults ages 20 to 35 and those ages 73 to 106.

When researchers next examined REST in brain samples from individuals with Alzheimer’s, they found the protein was almost absent from cells of the prefrontal cortex and hippocampus, regions of the brain critical for functions including memory, concentration and decision-making.

A key clue that REST protected brain cells in Alzheimer’s came from an analysis of brain tissue along with decades of test scores on memory and cognition from the Religious Orders Study and the Rush Memory and Aging Project. Researchers found that REST was significantly higher in those with Alzheimer’s brain abnormalities who didn’t develop dementia compared with those whose disease led to cognitive decline.

“Amyloid and tau may not be enough to trigger dementia,” Yankner said. “You would have to have a failure of stress response in the brain. Trying to eliminate these proteins might get you some of the distance but may not be optimally effective until you can increase the resilience of the brain to resist toxic stresses.”

To contact the reporter on this story: Angela Zimm in Boston at azimm@bloomberg.net

To contact the editors responsible for this story: Reg Gale at rgale5@bloomberg.net Andrew Pollack, Bruce Rule

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