Author response: The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

Abstract

Individuals with Alzheimer’s disease generally have deposits known as “amyloid plaques” in the brain. These plaques are made up of a mixture of molecules called amyloid beta peptides that clump together and are thought to be a key cause of the disease. The amyloid beta peptides vary in size; the larger peptides tend to be more prone to forming clumps than the smaller ones and are thus more toxic to the brain. An enzyme called gamma-secretase makes amyloid beta peptides by cutting up a protein called APP. Proteins are made of chains of building blocks called amino acids and studies using a technique called mass spectrometry show that gamma-secretase cuts APP in segments of three amino acids at a time. The size of the amyloid beta peptides produced is determined by the positions in APP that gamma-secretase selects to cut. Therefore, understanding how the enzyme works could provide new opportunities for developing drugs to treat Alzheimer’s disease. Here, Bolduc et al. found that the human gamma-secretase enzyme has sites that amino acids in APP can bind to that help to guide the enzyme to cut APP by three amino acids at a time. These binding sites control where the enzyme cuts APP and therefore determines which amyloid peptides are produced. Previous studies have linked several naturally occurring mutations in the gene encoding APP to inherited forms of Alzheimer’s disease. Bolduc et al. now reveal that several of these mutations affect the places that gamma-secretase cuts APP to produce amyloid peptides. These findings may be helpful for developing drugs that could manipulate gamma-secretase to produce smaller, less harmful amyloid peptides. Gamma-secretase can cut many other proteins, and so a future challenge will be to find out if the enzyme cuts these other proteins in the same way that it cuts APP.