Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases

Abstract Mutations in the presenilin (PS) genes PS1 and PS2are involved in Alzheimer’s disease (AD). Recently, apoptosis-associated cleavage of PS proteins was identified. Here wedemonstrate that PS1 as well as PS2 are substrates for differentmembers of the caspase protein family. Remarkably, thecaspases acting on PS1 could be subdivided in two groups. Onegroup, containing caspase-8, -6 and -11, cleaved PS1 afterresidues ENDD 329 and to a lesser extent after residuesAQRD 341 . A second group consisting of caspase-3, -7 and -1acted uniquely on AQRD 341 . Importantly, these two cleavagesites were also recognized by caspases in the C-terminal PS1fragment produced by constitutive proteolysis. In decreasingorder of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 atthe recognition site D 326 SYD 329 . Caspase-8 and -3 exhibited thehighest proteolytic activity on both PS1 and PS2. PS1 and PS2were not hydrolyzed by caspase-2 and PS2 also not by caspase-11. None of five missense mutations affected the sensitivity ofPS1 to caspase-mediated cleavage. This suggests that ADpathogenesis associated with PS1 missense mutations cannot beexplained by a change in caspase-dependent processing.z 1999 Federation of European Biochemical Societies.Key words: Alzheimer’s disease; Caspase; Cleavage;Presenilin; Substrate1. IntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder ofthe central nervous system leading to dementia and ultimatelyto death. AD cases usually occur sporadically, although ge-netic factors play an important role in at least half of thecases. Three AD genes were identi¢ed causing early-onsetfamilial AD (age at onset 665 year): the amyloid precursorprotein gene [1], the presenilin-1 gene (PS1) [2] and the pre-senilin-2 gene (PS2) [3,4]. The majority of the mutations aremissense mutations and are found in PS1. In addition, apoli-poprotein E-4 is a risk factor for AD [5,6].The PS genes encode two homologous proteins (PS1/PS2)of approximately 450 amino acids having 67% similarity [2,4].PS1/PS2 most likely have eight transmembrane domains andare located in the endoplasmic reticulum, to a lesser extent inthe Golgi apparatus [7^10]. Two diierent types of proteolysiswere identi¢ed for PS1/PS2. Constitutional, tightly regulatedproteolysis occurs at and near residue M