Innovative new research led by a team from the University of Washington is suggesting a novel strategy to battle Alzheimer's disease. Synthetic peptides have been developed to inhibit the aggregation of the toxic proteins commonly associated with early stages of the disease.
It is fair to say research into a treatment for Alzheimer's disease is currently at a crossroads after hundreds of failed clinical trials. The vast majority of work has focused on ways to eliminate amyloid protein plaques in the brain, the most commonly hypothesized cause of the neurodegenerative decline associated with the disease.
A new study is claiming amyloid beta proteins may still be the culprit behind Alzheimer's progression, but the main damage happens long before the larger aggregations, known as plaques, accumulate. The earliest stages of amyloid protein dysfunction appear to be when the proteins begin misfolding and clumping together. As these misfolding proteins begin clustering they initially form what are called oligomers.
These amyloid oligomers can begin clustering for over a decade before larger amyloid plaques appear and it is often the presence of these toxic oligomers that better correlate with the cognitive impairment associated with Alzheimer's. The new research suggests it is these amyloid oligomers that are the primary toxic element behind Alzheimer's.
"Amyloid beta definitely plays a lead role in Alzheimer's disease, but while historically attention has been on the plaques, more and more research instead indicates that amyloid beta oligomers are the toxic agents that disrupt neurons," says Valerie Daggett, corresponding author on the new study.
So, to battle the disease, the scientists set out to develop a non-toxic synthetic peptide that can inhibit the formation of these amyloid oligomers. To do this the researchers first discovered that amyloid beta oligomers form a structure called an alpha sheet, before they cluster into larger plaques. This alpha sheet protein structure only occurs when proteins are misfolding.
The next step was to construct artificial alpha sheets from synthetic peptides. The plan was to use these synthetic alpha sheets to neutralize any damage that can be caused from the toxic amyloid oligomers, and block any further aggregation. So far the results are incredibly promising, with human cell culture and animal tests suggesting the technique is both safe and effective.
Mouse studies revealed the synthetic peptides actually reduced amyloid beta oligomer levels swiftly after a single dose. In C. elegans worms, a common laboratory model for Alzheimer's, the synthetic peptides effectively protected the worms from damage caused by bacteria designed to express amyloid beta proteins.
"This is about targeting a specific structure of amyloid beta formed by the toxic oligomers," explains Daggett. "What we've shown here is that we can design and build synthetic alpha sheets with complementary structures to inhibit aggregation and toxicity of amyloid beta, while leaving the biologically active monomers intact."
All of this research is still a way off becoming a safe and viable human treatment, but the work is certainly promising, and the team is further refining the synthetic compounds to be even more efficient at clearing out amyloid beta oligomers. In addition, the study also points to ways the alpha sheet technique can be used to measure toxic oligomer levels, pointing the way to a potential diagnostic test for Alzheimer's that could identify patients years before any symptoms appear.
"What we're really after are potential therapeutics against amyloid beta and diagnostic measures to detect toxic oligomers in people," concludes Daggett.
The new study was published in the journal PNAS.
Source: University of Washington
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