Researchers have known that the peptide amyloid beta plays a role in causing Alzheimer's disease, but they are still working to determine how it becomes toxic.
Bieschke, assistant professor of biomedical engineering in the School of Engineering & Applied Science, and his collaborators found that the amyloid beta protein structure that was able penetrate the cell had a specific type of beta sheet in which its peptides stacked onto each other, similar to a layer cake.
"Somewhere on this aggregation pathway, this type of structural element is formed for the amyloid beta to get into the cell," Bieschke said. "There is a two-step process: amyloid beta can bind to the membrane and form aggregates while on the surface of the cell, then it gets taken up into the cell."
Alzheimer's researchers have had a long-standing debate on whether amyloid beta is toxic before entering the nerve cell or after entering the cell. Amyloid beta can interfere with the mitochondria, or the cell's energy powerhouse. This causes the cell to stop breathing and leads to eventual cell death. Studies of patients with late-stage Alzheimer's disease reveal the death of many nerve cells in the brain.
With this knowledge, Bieschke and his collaborators can investigate what happens next to amyloid beta once inside the cell and how it interacts with the mitochondria.
"We will determine if we can see and measure the interaction with the mitochondria membrane, and if these structures are interacting with mitochondria the same way as with the outer cell membrane," he said. "Another question we will ask is: Can we manipulate the uptake or formation of these structures so they cannot enter the cell? This may be a therapeutic strategy to help future patients with Alzheimer's."
The School of Engineering & Applied Science at Washington University in St. Louis focuses intellectual efforts through a new convergence paradigm and builds on strengths, particularly as applied to medicine and health, energy and environment, entrepreneurship and security. With 88 tenured/tenure-track and 40 additional full-time faculty, 1,300 undergraduate students, more than 900 graduate students and more than 23,000 alumni, we are working to leverage our partnerships with academic and industry partners — across disciplines and across the world — to contribute to solving the greatest global challenges of the 21st century.
Funding for this research was provided by German Research Foundation, NBGN-Plus, IG Neuronet, Wissenschaftliche Plattform Interaktom, and the Diabetes Research Center at Washington University in St. Louis (National Institutes of Health Grant No. 5 P30 DK020579).
Jin A, Kedia N, Illes-Toth E, Haralampiev I, Prisner S, Herrmann A, Wanker E, Bieschke J. Amyloid-b1-42 aggregation initiates it cellular uptake and cytotoxicity. Journal of Biological Chemistry, Sept. 9, 2016.