Scientists say they have identified—and shown that it may be possible to control—the mechanism that leads to the rapid buildup of the disease-causing plaques that are characteristic of Alzheimer's disease.
In Alzheimer’s, protein fibrils (amyloids) become intertwined and entangled with each other, causing the so-called plaques that are found in the brains of Alzheimer's patients. Spontaneous formation of the first amyloid fibrils is slow and typically takes several decades, which could explain why Alzheimer's is usually a disease that affects people in their old age. However, once the first fibrils are formed, they begin to replicate and spread much more rapidly by themselves, making the disease extremely challenging to control.
Despite its importance, the fundamental mechanism of how protein fibrils can self-replicate without any additional machinery is not well understood. In a study (“Physical Determinants of the Self-Replication of Protein Fibrils”) published in Nature Physics, a team led by researchers from the department of chemistry at the University of Cambridge used a combination of computer simulations and laboratory experiments to identify the necessary requirements for the self-replication of protein fibrils.
The researchers found that the seemingly complicated process of fibril self-replication is actually governed by a simple physical mechanism: the buildup of healthy proteins on the surface of existing fibrils. The investigators used amyloid-β, which forms the main component of the amyloid plaques found in the brains of Alzheimer's patients. They found a relationship between the amount of healthy proteins that are deposited onto the existing fibrils and the rate of the fibril self-replication. In other words, the greater the buildup of proteins on the fibril, the faster it self-replicates.
They also showed, as a proof of principle, that by changing how the healthy proteins interact with the surface of fibrils, it is possible to control the fibril self-replication.
“One of the mysteries of amyloid plaque formation is how, after their long, slow formation, the speed of their progression becomes much faster,” said Andela Šaric, Ph.D., the study’s first author. “We've identified the factors that in fact cause the system to catalyze its own activity, becoming a runaway process. But this discovery suggests that if we're able to control the buildup of healthy proteins on the fibrils, we might be able to limit the aggregation and spread of plaques.”
Dr. Šaric also argued that the findings could be of great interest in the field of nanotechnology, noting that “One of the unfilled goals in nanotechnology is achieving efficient self-replication in manufacturing of nanomaterials. This is exactly what we've observed happening with these fibrils. If we're able to learn the design rules from this process, we may be able to achieve this goal.”