WASHINGTON, D.C.: Much of the research on Alzheimer’s disease has focused on the amyloid beta protein, which clumps together into sticky fibrils that form deposits in the brains of people with the disease. In recent years, attention has turned away from the fibrils themselves to an intermediate stage in the aggregation of amyloid beta. “Oligomers” consisting of a few molecules of the protein stuck together are more mobile than the large, insoluble fibrils and seem to be much more toxic. But the actual structure of these soluble oligomers remains unknown, and it’s unclear how they trigger the neurotoxic effects that lead to Alzheimer’s disease.
A new study by researchers at UC Santa Cruz may help lift the veil on the structure and behavior of these neurotoxic oligomers. The researchers made a subtle alteration to the amyloid beta protein that had striking effects on its properties. By replacing one amino acid with its mirror image, they created a version of amyloid beta with a reduced rate of fibril formation, different fibril structure, and increased toxicity in cell culture compared to the normal or “wild type” protein.
“We perturbed the system very slightly and got enhanced cytotoxicity and destabilization of fibrils,” said Jevgenij Raskatov, assistant professor of chemistry and biochemistry at UC Santa Cruz…