Treating dementia disorders such as Alzheimer’s disease remains one of the greatest challenges facing modern medicine. During the course of neurodegenerative diseases, certain proteins, such as the amyloid β protein, accumulate in the brain. They are suspected to be associated with the development of the disease, and therefore they are considered a promising target for therapeutic approaches.
It is already known that the misfolded proteins clump together and form fibrous structures. However, it is not yet fully understood how these fibrils are formed. Now a team led by Empa researcher Peter Nirmalraj from Empa’s Transport at Nanoscale Interfaces laboratory and scientists from Ireland’s University of Limerick have been able to show how the process takes place using a particularly powerful imaging technique. The special thing about it: some of the nanometer-thin fibrils apparently ensure the spread of the disease in the brain tissue and are therefore called “superspreaders”. The researchers recently published their findings in the scientific journal Science Advances.
Poisonous subspecies
This peculiar subspecies of protein fibrils attracted the attention of researchers because of its unusual properties: the edges and surfaces of the so-called superspreader fibrils show particularly high catalytic activity. New protein building blocks accumulate in these very active sites. As a result, new long-chain fibrils form from these nucleation sites. The researchers assume that these second-generation fibrils eventually spread and form new aggregates in the brain.
The chemical composition of the misfolded amyloid β protein is known. The mechanism of how protein building blocks come together to form second-generation fibrils, as well as their shape and structure, was previously unclear.
Conventional methods, such as those based on staining techniques, could alter the morphology and adsorption site of the proteins so that they cannot be analyzed in their natural form.”
Peter Nirmalraj, Transport at Nanoscale Interfaces, EMPA
Unprecedented precision
The technique that the Empa researcher used in this new study is different: the proteins are analyzed unchanged in a saline solution, which is much closer to the natural conditions in the human body than is the case with conventional methods. The high-resolution atomic force microscope allows the fibrils, which are less than 10 nanometers thick, to be photographed with unprecedented precision at room temperature. The researchers were able to monitor the process of fibril formation in real time, from the first moments to the next 250 hours. The analyzes were then compared and supplemented with molecular model calculations. This allowed the fibrils to be classified into subpopulations such as “superspreader” based on their surface structures. “This work brings us one step closer to a better understanding of how these proteins distribute in Alzheimer’s disease brain tissue,” says Empa researcher Nirmalraj. He hopes this will eventually lead to new ways to monitor disease progression and diagnostic procedures.