The treatment of dementia disorders, including Alzheimer’s disease, remains one of modern medicine’s greatest challenges. In neurodegenerative diseases, certain proteins, such as amyloid β, accumulate in the brain and are believed to contribute to disease development, making them key targets for potential therapies.
Scientists know that these misfolded proteins can clump together into fiber-like structures, or fibrils. However, the exact process of fibril formation is still not fully understood. Recently, a research team led by Peter Nirmalraj from Empa’s Transport at Nanoscale Interfaces lab, in collaboration with researchers from the University of Limerick in Ireland, made significant progress in visualizing this process using a powerful imaging technique. Their work has shown that some nanometer-thin fibrils appear to play a significant role in spreading the disease in brain tissue. These fibrils, referred to as “superspreaders,” were highlighted in a recent article in Science Advances.
Toxic Superspreaders
The researchers observed a unique subspecies of fibrils, which they termed “superspreader fibrils,” due to its distinctive properties. These fibrils showed high catalytic activity along their edges and surfaces, attracting new protein building blocks that lead to the growth of long, chain-like fibrils. The team suspects that these second-generation fibrils continue to spread within brain tissue, forming new protein aggregates that could accelerate disease progression.
While the chemical makeup of the amyloid β protein is well-documented, the precise way these proteins clump to form second-generation fibrils—along with the structure and shape of these fibrils—has remained unclear until now.
New Imaging Precision
The Empa research team employed an advanced technique that maintains proteins in a salt solution, closely mimicking natural conditions in the human body, unlike traditional methods. Using a high-resolution atomic force microscope, they photographed the fibrils, which are less than 10 nanometers thick, with unmatched precision at room temperature. They observed fibril formation in real time over 250 hours, then supplemented these observations with molecular model calculations. This approach allowed them to categorize fibrils into subpopulations like “superspreader,” based on surface structures.
“This work brings us one step closer to understanding how these proteins spread in the brain tissue of Alzheimer’s patients,” said Empa researcher Nirmalraj. He hopes that the findings will eventually lead to improved ways of monitoring disease progression and developing new diagnostic procedures.
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