Researchers led by UW Department of Bioengineering Professor Valerie Daggett have developed synthetic peptides that can target and inhibit the small, toxic protein aggregates that are thought to trigger Alzheimer’s disease. The team reports their achievement in a paper published the week of April 15 in the Proceedings of the National Academy of Sciences.
Their synthetic peptides, which are designed to fold into a structure known as an alpha sheet, can block aggregation of amyloid beta, a brain protein, at its earliest and most toxic stages – as shown by experiments in human neural cell cultures, in mice and the common laboratory worm Caenorhabditis elegans. The results indicate that synthetic alpha sheets could form the basis of therapeutics to clear these small, toxic aggregates in people.
The team showed that the synthetic alpha sheet’s blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer’s. These findings add evidence to the growing consensus that amyloid beta oligomers — not plaques — are the toxic agents behind Alzheimer’s disease.
Ball-and-stick model of the structure of AP407, one of the synthetic alpha sheet peptides designed by the research team to inhibit toxic oligomers of amyloid beta. Shea et al., PNAS, 2019
“This is about targeting a specific structure of amyloid beta formed by the toxic oligomers,” explains Dr. Daggett in a UW News article. “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.”