200 Misfolded Proteins Linked to Cognitive Decline
New research suggests that misshapen proteins, beyond the well-known amyloids, are considerably contributing to age-related memory loss and cognitive impairment.
As individuals age, maintaining cognitive function and independence becomes a paramount concern. While amyloid plaques have long been the primary focus in understanding Alzheimer’s disease and other forms of dementia, groundbreaking research is shifting the spotlight to a broader spectrum of molecular culprits.
The “Tip of the Iceberg”: Misfolded Proteins Beyond Amyloids
“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 Stephen Fried, an assistant professor of chemistry and protein scientist at Johns Hopkins university. “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.”
Fried’s team’s recent findings, published in Science Advances, indicate that amyloids may represent only a fraction of the molecular issues affecting brain health during aging. “Our research is showing that amyloids are just the tip of the iceberg,” he states.
Understanding the Molecular Differences in Aging Brains
To delve deeper into the molecular distinctions between aging brains that remain sharp and those experiencing decline, Fried and his colleagues conducted a complete study. They examined 17 two-year-old rats, all raised in the same environment. This cohort was divided into two groups: seven rats that performed poorly on memory and problem-solving tests, indicating cognitive impairment, and ten rats that performed comparably to much younger, six-month-old rats, signifying cognitive health.
The researchers meticulously measured over 2,500 types of proteins within the hippocampus, a critical brain region responsible for spatial learning and memory. This study marked a significant advancement, enabling scientists for the first time to identify whether individual proteins were misshapen or folded incorrectly across a large number of proteins. This allowed for a clear distinction between proteins that misfold generally with aging and those that specifically misfold in cognitively impaired individuals.
Identifying the Unseen Contributors to Cognitive Decline
The results were striking: more than 200 proteins were found to be misfolded in the cognitively impaired rats, while these same proteins maintained their correct shapes in the cognitively healthy rats. This strongly suggests that these specific misfolded proteins are actively contributing to cognitive decline.
Previously, the scientific community believed that misfolded proteins, particularly A-beta and tau proteins, were only detrimental when they aggregated into amyloid plaques. Though, this new research challenges that notion.
“We think there are a lot of proteins that can be misfolded, not form amyloids, and still be problematic,” Fried elaborates. “And that suggests these misfolded proteins have ways of escaping this surveillance system in the cell.”
Cells possess a natural surveillance system designed to identify and eliminate misbehaving, misfolded proteins to maintain proper function. The fact that these non-amyloidogenic misfolded proteins are present and impactful implies they are evading this crucial cellular defense mechanism.
Future Directions: Illuminating Molecular Deformities
The exact mechanisms by wich these misfolded proteins bypass cellular security systems remain an area of active investigation. Fried’s team plans to utilize high-resolution microscopy to gain a more detailed understanding of the specific deformities of these proteins at the molecular level.
“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 reflects. “Understanding what’s physically going on in the brain could lead to better treatments and preventive measures.”
By expanding our understanding beyond amyloids to encompass the broader landscape of misfolded proteins, this research opens new avenues for developing more effective strategies to combat age-related cognitive decline and preserve brain health throughout life.