Scientists know the peptide amyloid beta plays a role in Alzheimer’s disease, but it’s not clear how or when it becomes toxic.
Now they have discovered that amyloid beta must change its internal structure into a long, flat structure called a beta sheet to be absorbed into the cell.
Peptides stacked onto each other, similar to a layer cake.
The findings, published in the Journal of Biological Chemistry, show the amyloid beta protein structure that was able to penetrate the cell had a specific type of beta sheet: 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, says Jan Bieschke, assistant professor of biomedical engineering at Washington University in St. Louis. “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, researchers 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,” Bieschke says.
“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.”