While a decisive cure is yet to be found for Alzheimer’s disease, research is offering up ways that it could be slowed or even have its symptoms reversed. The latest cause for hope involves a naturally occurring molecule that researchers have found can serve as an inhibitor, intervening to halt progress of the disease during its formative stages.
The onset of Alzheimer’s disease is believed to correlate with the accumulation of brain plaques, a buildup of toxic protein clusters called oligomers that cause irreparable damage to the synapses and lead to symptoms such as memory loss. The Cambridge team, much like a number of other research efforts around the world, is examining this process to ascertain where, if at all, it might be halted.
The first stages of this degeneration involve badly behaving proteins folding into the wrong shapes and then clumping together. Called amyloid fibrils, these proteins trigger a chain reaction, causing other proteins with which they come into contact to follow the same model, resulting in the dangerous oligomer clusters. The researchers call this stage secondary nucleation, and once triggered, it snowballs into larger quantities of toxic clusters and ultimately results in Alzheimer’s disease.
Through an extensive examination of these molecular processes, the researchers were able to model the sequence of events during the onset of Alzheimer’s disease. Further, they were able to model what might occur should one of the steps be shut off.
"We had reached a stage where we knew what the data should look like if we inhibited any given step in the process, including secondary nucleation," says Dr Samuel Cohen, lead author of the report. "Working closely with our collaborators in Sweden, who had developed groundbreaking experimental methods to monitor the process, we were able to identify a molecule that produced exactly the results that we were hoping to see in experiments."
Called Brichos, the molecule was found to prevent secondary nucleation. It does so by binding to the surface of amyloid fibrils, providing a shield coating that prevents contact with other proteins that causes them to misfold and culminate in toxic oligomers. According to the researcher's models, this would make the onset of Alzheimer’s "much slower and far less devastating."
The natural molecule (in black) coats the amyloid fibrils to stop it coming into contact with other proteins (Image: S. Cohen/University of Cambridge)
The team tested the effects of the molecules in the brains of mice exposed to amyloid proteins, proteins which would normally lead to an increase in toxicity in the tissue. But the researchers found that when they brought the newly identified molecule into the mix, the proteins still folded into the wrong shape, but did so without increasing toxicity. This demonstrated to the researchers that it was indeed the molecule halting this chain reaction.
How exactly this molecule could be adapted as a drug to treat Alzheimer's disease isn't exactly clear, but the researchers say they have unearthed a strategy that may eventually allow them to apply the brakes to the dispiriting disease.
"It may not actually be too difficult to find other molecules that do this, it’s just that it hasn't been clear what to look for until recently," says Cohen. "It's striking that nature, has evolved a similar approach to our own by focusing on very specifically inhibiting the key steps leading to Alzheimer's. A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy."
The research team comprised researchers from the Department of Chemistry at the University of Cambridge, the Karolinska Institute in Stockholm, Lund University, the Swedish University of Agricultural Sciences, and Tallinn University. Their findings are reported in the journal Nature Structural & Molecular Biology.
Source: University of Cambridge