UW Bioengineering faculty Valerie Daggett

UW Bioengineering Professor Valerie Daggett

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.

Valerie Daggett alpha sheet structure

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.”

Lead author is Dylan Shea, a UW doctoral student in molecular engineering. In addition to Dr. Daggett, who is also a faculty member in the UW Molecular Engineering & Sciences Institute, co-authors are UW bioengineering undergraduate students Cheng-Chieh Hsu, Timothy Bi, Natasha Paranjapye and doctoral student Matthew Childers; Joshua Cochran and professor Gabriele Varani in the UW Department of Chemistry; Colson Tomberlin and associate professor Christopher Link with the University of Colorado Boulder; Libo Wang and Jeffrey Zondermanwith Redshift BioAnalytics; and Daniel Paris and executive director Mike Mullan with the Roskamp Institute.