In vitro gamma-secretase cleavage of the Alzheimer's amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc

Abstract

The γ-secretase complex mediates the final proteolytic event in Alzheimer's disease amyloid-β biogenesis. This membrane complex of presenilin, anterior pharynx defective, nicastrin, and presenilin enhancer-2 cleaves the C-terminal 99-amino acid fragment of the amyloid precursor protein intramembranously at γ-sites to form C-terminally heterogeneous amyloid-β and cleaves at an ε-site to release the intracellular domain or ε-C-terminal fragment. In this work, two novel in vitro γ-secretase assays are developed to further explore the biochemical characteristics of γ-secretase activity. During development of a bacterial expression system for a substrate based on the amyloid precursor protein C-t..