Alzheimer's cause found in trigger of brain protein malfunction

In a new breakthrough to find the cause of Alzheimer's disease, scientists have pinpointed a molecule that appears to trigger a chain reaction of protein malfunction that eventually clogs up and kills brain cells.

The teams, from the University of Cambridge in the UK and Lund University in Sweden, write about their findings in a paper due to be published online first this week in the Proceedings of the National Academy of Sciences.

Tuomas Knowles, one of the study leaders, runs a group based at Cambridge that studies the physical aspects of protein molecule self-assembly. In a statement about the study, he says current therapies for Alzheimer's and dementia are limited, they don't address the disease, only the symptoms:

"We have to solve what happens at the molecular level before we can progress and have real impact," he adds.

And that is what the researchers on this study did: they dug deep into molecular behavior and produced a detailed map of the pathway that produces the malformed proteins that are at the root of neurodegenerative disorders like Alzheimer's.

They believe their breakthrough is an important step toward earlier diagnosis of neurological disorders like Alzheimer's and Parkinson's.

And by revealing molecular clues about the earliest stages of Alzheimer's, they say the findings also open new avenues for developing drugs that target these pathways in the early stages of the disease.

Misfolding Proteins and Amyloid Fibrils

When proteins made in brain cells start to misfold and take on structures that cause them to malfunction, the end result is neurodegenerative diseases like Alzheimer's.

Proteins are important molecules for carrying out essential jobs in and around cells. To make a protein, the cell assembles amino acids according to patterns encoded in its DNA. The assembled protein is a long thin chain that is then folded into a complex, tightly packed and precise structure so it can carry out its tasks correctly.

Things start to go wrong when proteins misfold. These can then snag surrounding proteins, even if they are normal, producing clumps that can build up to millions of protein molecules, forming unwieldy tendrils called "amyloid fibrils".

Amyloid fibrils are what produce the large protein deposits or "plaques" found in the brains of people with Alzheimer's. These were thought to be the primary cause of the disease, until another senior author of this latest study, Christopher Dobson, a professor of Chemistry at Cambridge, and his team discovered "toxic oligomers" about ten years ago.

Toxic Oligomers and Juvenile Tendrils

When the abnormal amyloid fibrils that lead to plaques start to grow, the tendrils grow outwards around the starting or focal point. This is known as "nucleation".

When these were first discovered, it was thought that the key to the cause of Alzheimer's was this nucleation process. But that is only part of the story.

What this study shows is that once a small but critical amount of malfunctioning protein clumps together, it triggers a runaway chain reaction that leads to rapid formation of new clumps, activating new focal points through "nucleation".

And it appears it is these secondary nucleations that create juvenile tendrils that at first have just a few clusters containing a handful of protein molecules, or "toxic oligomers". (An oligomer, comprising only a few molecular units, is a much shorter version of a polymer, a repeating chain of units that can almost go on for ever).


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