Generation of Amyloid β Protein from a Presenilin-1 and βAPP Complex☆

Presenilin-1 (PS1) is a causative gene in early onset familial Alzheimer's disease (FAD). FAD-linked mutant PS1s significantly increased Aβ40 and Aβ42(43) levels (P < 0.001) and decreased the production of an 11.4 kD (β-stub) and an 8.7 kD (α-stub) carboxyl-terminal fragment of amyloid β precursor protein (βAPP-CTFs) (P < 0.01). In the 2% CHAPS extracted lysates, the complex containing the amino-terminal fragment of PS1 (PS1-NTF), the carboxyl-terminal fragments of PS1 (PS1-CTF), and βAPP-CTFs was identified. Incubation of this isolated complex at pH 6.4 showed the direct generation of Aβ40 and γ-stub from this complex. This reaction was inhibited by a γ-secretase inhibitor. The degrading rate of a co-precipitated β-stub was facilitated under the presence of FAD-linked mutant PS1s. This findings suggest that the direct generation of Aβ from the complex may play an important role in the pathogenesis of Alzheimer's disease.