Breakthrough in Understanding Alzheimer's Disease Onset: Catalytic Trigger Discovered

Researchers may have made a breakthrough when it comes to understanding the onset of Alzheimer's disease. They've discovered a catalytic trigger when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain.

Alzheimer's disease can devastate families as men and women struggle with cognitive difficulties. The disease itself occurs when normal structures of protein molecules within cells become corrupted. This, in turn, causes a neurodegenerative process that eventually leads to death.

Protein molecules are made in cellular "assembly lines" that join together chemical building blocks called amino acids in an order encoded to our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological functions.

Unfortunately, proteins can "misfold" under certain conditions. They can snag surrounding normal proteins, which then tangle and stick together in clumps which eventually build to masses, frequently millions, of malfunctioning molecules. These molecules then shape themselves into unwieldy protein tendrils.

Known as "amyloid fibrils," these abnormal tendril structures grow outward around the location where the focal point of these abnormal "species" occurs. The amyloid fibrils in turn can form the foundations of huge protein deposits, also known as plaques, that can be seen in the brains of Alzheimer's patients. These plaques aren't the cause of the disease, though. Instead, toxic oligomers that spread easily through the brain are the real culprits. They can kill neurons and interact harmfully with other molecules. Yet exactly how these oligomers formed was a mystery.

In order to find out, researchers brought together kinetic experiments with a theoretical framework based on master equations. They found that, surprisingly, once a small but critical level of malfunctioning protein "clumps" have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites. This, in turn, activates new focal points through nucleation.

This secondary nucleation process forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. It's these molecules that are known as oligomers.

"With a disease like Alzheimer's, you have to intervene in a highly specific manner to prevent the formation of the toxic agents," said Tuomas Knowles, lead author of the study. "Now we've found how the oligomers are created, we know what process we need to turn off."

The findings could have huge implications for the treatment of Alzheimer's disease. It's opened up future possibilities for a new generation of targeted drugs that could potentially slow the debilitating disease.

The findings are published in the journal Proceedings of the National Academy of Sciences.