Beyond Amyloids: New Research Uncovers Hundreds of Misfolded Proteins Linked to Cognitive Decline
A groundbreaking study reveals that hundreds of misfolded proteins, beyond the well-known amyloid plaques, may play a critical role in age-related cognitive decline, offering new avenues for Alzheimer’s and dementia treatment.
For decades, Alzheimer’s research has largely focused on the accumulation of A-beta and tau amyloids in the brain – protein clumps known to damage neurons and impair brain function. However, new findings suggest these visible plaques may represent only a fraction of the molecular changes occurring as the brain ages. The research, published in Science Advances, could revolutionize our understanding of neurodegenerative diseases and pave the way for more effective therapies.
“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 a leading protein scientist involved in the study. “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.”
The research team, led by Stephen Fried, an assistant professor of chemistry at Johns Hopkins University, studied 17 rats to understand the molecular differences between healthy aging and cognitive decline. Seven rats exhibited impaired memory and problem-solving skills, while the remaining ten maintained cognitive function comparable to younger animals. Researchers meticulously analyzed over 2,500 proteins in the hippocampus, the brain region crucial for spatial learning and memory.
For the first time, scientists were able to identify which proteins were misshapen or incorrectly folded in each rat, differentiating between proteins that misfold with general aging and those specifically linked to cognitive impairment. The results were striking: more than 200 proteins were found to be misfolded in the cognitively impaired rats, while maintaining their correct shape in the healthy animals. This suggests a direct correlation between these specific misfolded proteins and cognitive decline.
Misfolded proteins disrupt cellular function because they are unable to perform their intended tasks. Cells possess a natural “surveillance system” to identify and eliminate these faulty proteins. Previously, it was believed that misfolded proteins only caused damage when they aggregated into amyloids. However, this study indicates that misfolded proteins, even without clumping, can be problematic.
“We think there are a lot of proteins that can be misfolded, not form amyloids, and still be problematic,” the scientist stated. “And that suggests these misfolded proteins have ways of escaping this surveillance system in the cell.”
The precise mechanisms by which these misfolded proteins evade the cell’s quality control system remain unclear. The team plans to utilize high-resolution microscopy to examine the molecular structure of these deformed proteins, gaining a more detailed understanding of their abnormalities. .
The implications of this research extend to the millions of individuals over 65 affected by Alzheimer’s, dementia, and other age-related cognitive diseases. Understanding the underlying molecular processes driving cognitive decline is crucial for developing targeted treatments and preventative measures.
“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,” Fried says. “Understanding what’s physically going on in the brain could lead to better treatments and preventive measures.”
Source: Johns Hopkins University
