Such disorders represent one of the greatest challenges to the social fabric and health care systems of much of the modern world, says Christopher Dobson from the University of Cambridge. Speaking at the 19th IUPAB and 11th EBSA Congress in Edinburgh last week, Dobson discussed the underlying molecular nature of Alzheimer's disease, and examined how emerging knowledge could help develop new therapies to combat its onset and progression. "It's a global challenge that we have to address with great urgency," he explained.

Protein misfolding disorders

Alzheimer's disease is known to arise from protein misfolding. Proteins – of which there are approaching 100,000 different types that are responsible for almost all processes within the human body – comprise long chains of amino acids connected in a sequence that is distinct to each protein type. In order to function, most of these chains need to fold into a unique 3D structure, with the folding instructions encoded into the amino acid sequence. "Folding and self-assembly are the essence of life," Dobson told the audience. "Our proteins have to fold properly and end up assembling into the right structures in order to function properly."

If proteins are misfolded, however, this can lead to a wide range of diseases, from cancers to diabetes. One major problem that arises from misfolding is aggregation of the affected proteins, which can result in so-called amyloid disorders. There are some 50 different types of such conditions, with each disease related to the nature of the protein involved and the site of the resulting deposits. All are incurable, and most are currently largely untreatable.

Alzheimer's disease, for instance, arises from the aggregation within the brain of plaques of the amyloid-beta protein, as well as tangles of the tau protein. Other examples include cardiac amyloidosis, where the deposits occur in the heart, and systemic amyloidoses, in which large quantities of proteins accumulate in organs such as the liver, kidney or spleen.

Dobson noted that in all of these diseases, the amyloid deposits are highly similar in structure – thread-like fibrils of a few microns in length and 10 nm diameter. "It turns out that there is an inherent tendency for our proteins to convert from their functional state into this pathological amyloid state," said Dobson. "Fortunately, this process is very slow, and is very carefully controlled in living systems."

Amyloid fibrils are typically extremely tough, and the force associated with their formation can disrupt tissue and vital organs. Under normal circumstances, however, cellular "housekeeping" mechanisms combat protein misfolding and neutralize their potentially devastating effects. But if such mechanisms fail, aggregates can accumulate. As well as generating problems by being non-functional and disruptive, when proteins start to convert into amyloid clumps they can generate toxic species that cause cell death.

To illustrate the origins and effects of aggregation in vivo, Dobson and colleagues inserted a protein that causes Alzheimer's in humans into Drosophila (fruit flies), and then generated mutations to make some variants of the protein more prone to aggregation than others. They then tested the flies' mobility and observed that those containing even slightly more aggregation-inclined proteins experienced far greater neuronal damage – exhibited by their inability to move in a normal manner.

Biology steps in

So how do living systems control such processes and can we exploit such mechanisms for therapeutic purposes? Amyloid formation involves a series of coupled events – including primary nucleation, elongation, fragmentation and secondary nucleation. Dobson and colleagues – notably Michele Vendruscolo and Tuomas Knowles in Cambridge, and Sara Linse in Lund in Sweden – examined this complex process for the Alzheimer's associated protein and assessed the relative rate constants of each step.

"We discovered, much to our surprise, that the process of primary nucleation wasn't the rate-determining one," said Dobson. Rather, once aggregation starts, secondary nucleation catalyses the creation of more aggregates, leading to their rapid proliferation. Thankfully, he explained, biology has found ways to prevent this runaway process, for example by using "molecular chaperones" to supress the process of secondary nucleation.

Such chaperones achieve this control by binding to the surfaces of the fibrils, so that they no longer act as sites to catalyse the secondary nucleation step. Meanwhile, other chaperones inhibit other steps, such as the primary nucleation process. "It's like a military operation, the system tries to stop the first step in the process but if the defences are breached, reinforcements are available to tackle the second step, and so on," explained Dobson. "So the question is can we exploit this type of approach for therapy?"

With this aim, Dobson and his colleagues in Cambridge and Lund are working to discover drug-like molecules that can inhibit specific steps in the amyloid formation process and so help prevent its onset – or, if aggregates have started to form, to control its spreading. He noted that the team has already found a range of molecules that are effective under laboratory conditions and have now set up a research programme to see whether they inhibit the aggregation process in living systems.

The researchers are already studying a model organism – the nematode worm – to screen compounds found to be potential inhibitors. Dobson described a study in which worms containing aggregated proteins, and were paralysed as a result, were treated with such compounds. The worms were able to move normally again, demonstrating the ability of the compounds to protect key cellular functions from the cytotoxic effects of the aggregates.

"This is incredibly good news," said Dobson. "And we are now taking this programme further through a new Centre for Misfolding Diseases recently established in Cambridge, and then moving towards the development of drugs for humans, particularly through a start-up company called Wren Therapeutics."

"In summary, we are bringing scientists and techniques from a wide range of disciplines together to discover the ways that protein misfolding and aggregation occurs, to discover how biology controls such processes, and then to mimic the way that it does – ideally by using small molecules to generate effective and widely available drugs to treat and prevent this devastating '21st-century plague'. With the ever increasing power of modern science, illustrated so clearly by this exciting conference in Edinburgh, I'm incredibly optimistic for the future," Dobson concluded.

Related stories

• Advanced tools progress neuroscience research
• Biophysics: opening up new areas of biological science
• Can radiotherapy treat Alzheimer's disease?
• Smartphones search for Alzheimer's cure