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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).

These "toxic oligomers" are soluble and small enough, unlike the bigger, insoluble and denser plaques (which have more of a knotted polymer structure), to travel around the brain and wreak havoc by interacting harmfully with other molecules. The result is the gradual death of neurons that cause loss of memory and the other known symptoms of dementia.

Before this study scientists knew that toxic oligomers were more likely to be the cause of Alzheimer's, but were mystified about where they came from.

Knowles says:

"We've now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene - the molecular catalyst that underlies the pathology." Recreating the Crime Scene at the Root of Alzheimer's The researchers brought together tools commonly used in other areas of chemistry and physics, but this study is the first time they have been used to their full potential to look at misfolding proteins.

"Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results," says Knowles.

He explains that they are essentially borrowing tools from chemistry and physics to look at a biomolecular problem: to map the networks of processes and "recreate the crime scene" that is at the molecular root of Alzheimer's.

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

In another breakthrough study published recently researchers suggest new Alzheimer's treatment may come from discovering how plaques lead to tangles.

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