Blocking the cleavage at midportion between γ‐ and ε‐sites remarkably suppresses the generation of amyloid β‐protein

Abstract

To examine how γ‐ and ε‐cleavages of β‐amyloid precursor protein (APP) are related, each cleavage site was replaced with a stretch of Trp that cannot be cleaved by γ‐secretase. Replacement of the γ‐ or ε‐site significantly suppressed secretion of amyloid β‐protein (Aβ), and produced longer Aβ or longer APP intracellular domain, respectively. This cleavage at the midportion between γ‐ and ε‐sites was also γ‐secretase‐dependent. Blocking this cleavage with a Trp stretch remarkably suppressed Aβ generation, indicating that the midportion cleavage is required for the generation of Aβ.