In diseases like Alzheimer’s, the accumulation of misfolded proteins in the brain poses significant challenges. Recently, researchers have made significant strides in understanding a particularly active type of protein fibrils with exceptional precision. They observed the production of potentially harmful molecules on the surfaces of these protein fibrils over a time span of hours, from initial to later stages.
Addressing dementia-related conditions, especially Alzheimer’s, remains one of the most daunting challenges in contemporary medicine. During the progression of neurodegenerative diseases, proteins such as amyloid β accumulate in the brain and are believed to play a crucial role in the disease’s development, making them a promising focus for treatment strategies.
It is known that these misfolded proteins cluster together to form thread-like structures known as fibrils. However, the exact process of fibril formation has not been completely understood. A research team led by Peter Nirmalraj at Empa’s Transport at Nanoscale Interfaces lab, along with scientists from the University of Limerick in Ireland, utilized a powerful imaging technique to shed light on this process. Remarkably, some of the extremely thin fibrils act as “superspreaders,” facilitating the disease’s propagation within brain tissue. Their findings were recently published in the scientific journal Science Advances.
Toxic subspecies
This distinctive class of protein fibrils drew the researchers’ attention due to its unique characteristics: The edges and surfaces of these “superspreader” fibrils exhibit notably high catalytic activity. Therefore, new protein building blocks gather at these highly reactive sites, resulting in the formation of longer fibrils from these initiation points. The researchers suspect that these second-generation fibrils eventually propagate and create new aggregates within the brain.
While the chemical composition of misfolded amyloid β is known, the exact mechanism by which these protein building blocks unite to create second-generation fibrils, along with their shape and structure, remain unclear. “Traditional methods, particularly those reliant on staining techniques, may alter the proteins’ morphology and adsorption sites, hindering analysis in their natural form,” explains Nirmalraj.
Unprecedented precision
The method employed by the Empa researcher in this study diverges from conventional approaches: The proteins are analyzed in a saline solution, mimicking more closely the natural conditions found in the human body. Utilizing a high-resolution atomic force microscope, the researchers captured images of fibrils less than 10 nanometers thick with remarkable precision at room temperature. They tracked the fibril formation process in real time, from the initial moments up to 250 hours. The data collected was cross-examined and enhanced with molecular modeling calculations, which allowed the classification of fibrils into subpopulations, like “superspreader,” based on their surface structures. “This research gets us one step closer to understanding how these proteins propagate within the brain tissue affected by Alzheimer’s disease,” states Nirmalraj. He expresses hope that these insights will lead to improved methods for monitoring disease progression and enhancing diagnostic processes.
This study was supported by the “Dementia Research Switzerland — Synapsis Foundation.”
