CORVALLIS, Ore. – An Oregon State University scientist and a team of undergraduate students have uncovered real-time insights into a chemical process linked with Alzheimer's disease, paving the way toward better drug designs.
The researchers used a molecule measuring technique to observe in a laboratory setting how certain metals can promote the protein clumping that leads to the blocked neural pathways associated with Alzheimer's.
Led by Marilyn Rampersad Mackiewicz , associate professor of chemistry in the OSU College of Science, the research team also watched molecules known as chelators disrupt or reverse the clumping.
Findings were published in ACS Omega .
Alzheimer's disease is the most common form of dementia, a chronic condition of impaired cognitive function that affects large numbers of older adults and their loved ones. According to the Centers for Disease Control and Prevention , Alzheimer's is the sixth-leading cause of death for people age 65 and older.
In Alzheimer's patients, aggregations of amyloid-beta proteins interrupt brain cells' ability to communicate with each other. The brain needs certain metals to work properly, but problems arise when the metals are present in unbalanced quantities.
"Too many of some metal ions, like copper, can interact with amyloid-beta proteins in ways that lead to protein aggregation, but most experiments have only shown the end result, not the interactions and aggregation process itself," Mackiewicz said. "We developed a method that lets us observe those interactions live, second by second, and directly measure how different molecules interrupt or reverse them. It shifts the question from 'does something work?' to 'how does it work, and when?'"
A chelator, whose name comes from the Greek word for claw, is a type of molecule able to bind with metal ions as if gripping them tightly.
One of the chelators in the study was shown, via a technique known as fluorescence anisotropy, to effectively snatch up metal ions, but in a non-selective way; i.e., it didn't differentiate between the types of metals that promote amyloid-beta aggregation and the types that don't.
However, the scientists observed the other chelator showing a strong ability to selectively grasp the copper ions believed to be a factor in Alzheimer's.
"That kind of real-time insight into how the protein aggregations form and unform is important for designing better treatments and for understanding why some widely used chemical approaches may not behave the way we assume they do," Mackiewicz said. "Alzheimer's affects millions of families and while clinical treatments based on this work remain years away, discoveries like this can offer genuine hope – with the correct targeting, some of the brain damage might be reversible."
Support from the SURE Science Program and donors Julie and William Reiersgaard made possible the research contributions of undergraduate students Alyssa Schroeder of OSU and Eleanor Adams, Dane Frost, Erica Lopez and Jennie Giacomini of Portland State University.
Mackiewicz says testing in more complex biological systems, including cellular and preclinical models, is the next step.
"Many potential Alzheimer's treatments fail due to an incomplete understanding of how amyloid-beta protein aggregation occurs," she said. "By directly observing and quantifying these interactions, our work provides a roadmap for creating more effective therapies."
