An empirical model of γ-secretase activity

γ-Secretase catalyzes the cleavage at the carboxyl terminus of Aβ to release it from the APP. While γ-secretase is a major therapeutic drug target for the treatment of Alzheimer's disease (AD), it appears to be an unusual proteolytic activity, and, to date, no protease responsible for this activity has been identified. Based on studies of APP transmembrane domain (TMD) mutants, it is apparent that there are multiple pharmacologically distinct γ-secretase activities that are spatially restricted and that presenilins (PS) regulate cleavage by γ-secretases in a protease independent fashion. Based on these studies, we propose a multiprotease model for γ-secretase activity and predict that the γ-secretases are likely to be closely related proteases.