Researchers at Virginia Commonwealth University (VCU) have found that the presence of two additional amino acids in the amyloid beta (Aβ) protein sequence forms the basis of amyloid plaque formation and Alzheimer’s disease development.
Their study, “Few Ramachandran Angle Changes Provide Interaction Strength Increase in Aβ42 versus Aβ40 Amyloid Fibrils,” appeared in the journal Scientific Reports.
Cleaving the Alzheimer precursor protein results in smaller protein sequences known as Aβ monomers. Scientists have established the aggregation of these Aβ monomers and their accumulation on brain cells as the cellular basis of Alzheimer’s. Yet they don’t fully understand how these neurotoxic Aβ plaques are formed or how to prevent them.
The Aβ monomers can have co-existing sequences of 42 amino acids; others with 40 amino acids are known to be less toxic. Although both the Aβ40 and Aβ42 monomers can cluster and originate in the amyloid plaques, the way these proteins interact is different.
The team led by Michael Peters, a professor at VCU’s Department of Chemical and Life Science Engineering, showed that the additional two amino acids in Aβ monomers sequence are essential in stabilizing amino amyloid aggregates and increasing toxicity.
“With diseases like cancer, you can have one or more mutations or sequence changes along the chain itself, which radically alters the protein’s behavior,” Peters said a VCU news release. “In the case of Alzheimer’s, there are no mutations in the monomers. You are simply adding only two natural amino acids to the very end of the non-toxic monomers, which causes a catastrophe.”
The Aβ40 monomers can stick to each other and form fibril stacks. As they add more and more monomers to their aggregates, the bonds between them weaken and break down.
Based on computational analysis the team discovered that adding the two amino acids at the end of Aβ sequence caused slight rotations that allowed Aβ42 to form stronger bonds among them, making their fibril stacks more resilient. This led to bigger plaque structures that have a bigger impact on neuronal function, and ultimately to cell death.
“It’s a literal twist of fate,” Peters said.
Based on this discovery, the researchers are investigating new drugs to disrupt the formation of Aβ42 molecules.
“We have to get therapeutic molecules across the rather impervious blood-brain barrier and inhibit fibril formation, while not being toxic to the body or interfering with normal bodily functions,” said Peters. “This makes for a very difficult three-fold problem, but we are making progress.”