While the cause of Alzheimer’s disease remains unclear, the accumulation of amyloid-beta proteins in the brain is still thought to be a major culprit. That's why amyloid-beta plaques and tau tangles—twisted fibers of the tau protein that form inside dying cells—are a prime target in Alzheimer’s research.
Now a University of Cambridge team is using computer-designed antibodies to stop amyloid-beta from sticking together and forming clumps.
Harmful brain deposits form when amyloid and tau proteins fold into the wrong shape and stick together. The designer antibodies target the amyloid-beta protein’s epitopes, which are the regions where antibodies bind. They block the protein’s ability to aggregate, resulting in the “almost complete elimination” of amyloid plaques in test tubes and in nematode worms, according to a statement. The research was published in Science Advances.
An Alzheimer’s treatment that prevents plaque formation and neuron loss would be a significant boost to the field, where treatments focus on managing symptoms and not on delaying or halting disease progression. Whileseveral antibody-based treatments for Alzheimer’s are available in the clinic, including AbbVie’s anti-tau candidate, ABBV-8E12, and Biogen’s amyloid-buster, aducanumab, the field has endured some late-stage failures. Merck terminated a 2,000-patient trial of its verubecestat after external reviewers deemed it had “virtually no chance of finding a positive clinical effect,” while Eli Lilly ditched its solanezumab last fall because it failed to beat out a placebo.
Antibodies are traditionally made by injecting animals with the antigen of interest, but technological improvements have made it possible to design them using a computer. This computer-aided design "substantially lowers the time and cost required," said study co-author Pietro Sormanni, a postdoctoral researcher in the Centre for Misfolding Diseases in Cambridge, in the statement. "It also allows us to target specific regions within the antigen, as well as to control for other properties critical for clinical applications, such as antibody stability and solubility."
The designer antibodies are smaller than traditional antibodies, the Cambridge researchers wrote, so they cross the blood-brain barrier more easily and do not provoke the inflammatory response that has limited the success of other antibody-based treatments for Alzheimer’s.