Molecular trigger for Alzheimer's identified

Cambridge researchers have pinpointed a catalytic trigger for the onset of Alzheimer's disease that leads to the death of neurons in the brain, paving way for early diagnosis of the neurodegenerative disease.
For the first time, scientists at University of Cambridge have been able to map in detail the pathway that generates "aberrant" forms of proteins which are at the root of conditions such as Alzheimer's.
They believe the breakthrough established by Professor Christopher Dobson opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer's that drugs could possibly target.

"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," said Dr Tuomas Knowles, lead author of the study.
Protein molecules are made in cellular 'assembly lines' that join together chemical building blocks called amino acids in an order encoded in 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 function.
Under some conditions, however, proteins can 'misfold' and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils.

The abnormal tendril structures, called 'amyloid fibrils', grow outwards around the location where the focal point, or 'nucleation' of these abnormal "species" occurs.

Amyloid fibrils can form the foundations of huge protein deposits - or plaques - long-seen in the brains of Alzheimer's sufferers, and once believed to be the cause of the disease, before the discovery of 'toxic oligomers'.
The new work, in large part carried out by researcher Samuel Cohen, shows that 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, activating new focal points through 'nucleation'.

It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules.
Small and highly diffusible, these are the 'toxic oligomers' that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.
The study was published in the Proceedings of the National Academy of Sciences.