The real cause of brain damage in Alzheimer’s patients may be proteins other than beta amyloid, according to a new study that may help develop therapies against this target.
Current theories about the origins of Alzheimer’s, the leading cause of dementia in older people worldwide, have been challenged by new findings from Emory University, as a team of researchers from the Goizueta Institute for Brain Health has found strong evidence supporting a new understanding of the mechanism behind the disease.
In a paper published in Cell Reports Medicine, Todd E. Golde and Yona Levites explain how amyloid beta deposits, long known to build up in the brains of Alzheimer’s patients, act as a kind of scaffolding for the buildup of other proteins. Because many of these proteins have known signaling functions, their presence around the amyloid clumps known as plaques could be the actual cause of brain damage rather than the amyloid itself.
In the brains of Alzheimer’s sufferers, amyloid builds up and forms sticky plaques that disrupt brain function and cause cognitive decline. The big mystery has been understanding exactly how this process occurs. The most widely accepted hypothesis is that the buildup of beta amyloid interferes with communication between cells and activates immune cells in a process that ultimately destroys brain cells.
A starting point for developing new therapies against Alzheimer’s
In the study, Golde, director of the Emory Center for Neurodegenerative Diseases at the Goizueta Institute, Levites, an associate professor at Emory University School of Medicine, and colleagues presented a new hypothesis that emphasizes a different role for beta amyloid, a simple protein that forms in all brains but is normally dissolved by natural processes.
In their experiments, they used cutting-edge analytical technologies to identify and measure the level of more than 8,000 proteins in human Alzheimer’s brains, as well as similar proteins in mice. Focusing on the proteins whose levels were most significantly increased, they identified more than 20 proteins that accumulate along with beta amyloid in both human Alzheimer’s brains and in mice with the disease. As their research continues, they suspect they will find more.
“Once we identified these new proteins, we wanted to know if they were simply markers of Alzheimer’s or if they could actually alter the deadly pathology of the disease,” Golde says. “To answer that, we focused on two proteins, midkine and pleiotrophin. Our research showed that they accelerated amyloid aggregation both in the test tube and in mice. In other words, these additional proteins may play an important role in the process that leads to brain damage rather than amyloid itself. This suggests that they could be the basis for new therapies for this terrible brain condition that has been frustratingly resistant to treatment over the years.”
Because this research proposes a novel process by which Alzheimer’s develops, it could also enable new approaches to discovering treatment targets for other diseases.
Although the underpinnings of Alzheimer’s have been known for more than a century, the search for a cure has been slow, often marked by repeated cycles of initially promising treatments that failed to work in trials, as well as continuing controversy over the theories that best explain how the disease damages the brain. As the researchers say, “The initial notion of a purely linear amyloid cascade is now recognized as simplistic. Studies have revealed the vast complexity of changes that occur over decades in people’s brains as Alzheimer’s pathologies emerge.”
Significantly, multiple types of amyloid buildup, in addition to amyloid beta, have been implicated in more than 30 human disorders affecting tissues and organs throughout the body. Because this new research proposes a novel process by which Alzheimer’s develops, it could also enable new approaches to discovering treatment targets for other diseases.
