Misfolded proteins are already known to assemble together to form fiber-like structures. However, it is not yet fully understood how these fibrils form. Now, a team led by Empa researcher Peter Nirmalraj from the Empa 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 brain tissue, and are therefore called “super-spreaders.” The researchers recently published their findings in the journal Science Advances in science.

Toxic subspecies

This particular subspecies of protein fibrils has attracted the attention of researchers due to its unusual properties: the edges and surfaces of the so-called superspreader fibrils exhibit particularly high catalytic activity. New protein blocks accumulate in these highly active sites. As a result, new long-chain fibrils form from these nucleation sites. The researchers hypothesize that these second-generation fibrils eventually spread and form new aggregates in the brain.

The chemical composition of misfolded amyloid β protein is known. The mechanism of how protein 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 proteins so that they cannot be analyzed in their natural form,” says Nirmalraj.

Unprecedented precision

The technique used by the Empa researcher in this new study is different: the proteins are analyzed unchanged in a salt solution, which is much closer to the natural conditions in the human body than is the case with conventional methods. With the high-resolution atomic force microscope, the fibrils, which are less than 10 nanometers thick, can be imaged with unprecedented precision at room temperature. The researchers were able to follow 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 fibrils to be classified into subpopulations such as “superspreader” based on their surface structures. “This work brings us another step closer to a better understanding of how these proteins spread in Alzheimer’s brain tissue,” says researcher Empa Nirmalraj. He hopes this will eventually lead to new ways to monitor disease progression and diagnostic procedures.

The study was funded by “Dementia Research Switzerland – Synapsis Foundation”.