A new study from John Hopkins University in the US has identified hundreds of misfolded proteins that may be contributing to Alzheimer’s and cognitive decline.
Traditionally, research into Alzheimer’s has been dominated by 2 amyloids, A-beta and tau. These amyloids, or clumps of misfolded proteins, can kill brain cells and cause cognitive decline.
Graphic rendition of a proteasome, which breaks down misfolded and damaged proteins inside a cell. Credit: Fried Lab, Johns Hopkins University.
However, this new research has uncovered more than 200 types of misfolded proteins in rats that might be associated with age-related cognitive decline.
“Our research is showing that amyloids are just the tip of the iceberg,” says Stephen Fried, an assistant professor of chemistry and protein scientist.
The team studied 17 rats who grew up in the same colony, 7 of which were cognitively impaired. The researchers then compared more than 2,500 types of proteins in the hippocampus, the part of the brain responsible for spatial learning and memory.
Fried and colleagues determined where individual proteins were misshapen or folded incorrectly. More than 200 proteins were misfolded in the cognitively impaired rats but not in the other 10 rats suggesting some of those misfolded proteins contribute to cognitive decline.
A misfolded protein can’t carry out the tasks necessary for a cell to function properly, so cells identify proteins that are misbehaving and destroy them.
“Amyloids are the buildup of misshapen proteins. They’re big and ugly and easy to see under the microscope, so it makes sense that they catch our attention,” explains Fried. “But we’re seeing hundreds of proteins misfolding in ways that don’t clump together in an amyloid and yet still seem to impact how the brain functions.”
According to the World Health Organisation, 57 million people worldwide had dementia, with Alzheimer’s disease being the most common form contributing to 60–70% of these cases.
In Australia, dementia is the second leading cause of death, with an estimated 433,300 people in the country currently living with the disease .
“A lot of us have experienced a loved one or a relative who has become less capable of doing those everyday tasks that require cognitive abilities,” says Fried. “Understanding what’s physically going on in the brain could lead to better treatments and preventive measures.”
The research, published in Science Advances, challenges the current understanding that misfolded proteins are only disruptive to the brain when they are found in amyloid clumps.
“We think there are a lot of proteins that can be misfolded, not form amyloids, and still be problematic,” says Fried “And that suggests these misfolded proteins have ways of escaping this surveillance system in the cell.”
The research team now plans to look at these misfolded proteins under high-resolution microscopes.
This will allow the team to get a more detailed picture of what their deformities look like at the molecular level in hopes of finding more effective treatments.