Differential Regulation of Amyloid Precursor Protein/Presenilin 1 Interaction during Ab40/42 Production Detected Using Fusion Constructs

Beta amyloid peptides (A[beta]) play a key role in the pathogenesis of Alzheimer disease (AD). Presenilins (PS) function as the catalytic subunits of [gamma]-secretase, the enzyme that releases A[beta] from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Familial Alzheimer disease (FAD)-linked PSEN mutations alter APP processing in a manner that increases the relative abundance of longer A[beta]42 peptides to that of A[beta]40 peptides. The mechanisms by which A[beta]40 and A[beta]42 peptides are produced in a ratio of ten to one by wild type presenilin (PS) and by which A[beta]42 is overproduced by FAD-linked PS variants are not completely understood. We generated chimeras of the amyloid precursor protein C-terminal fragment (C99) and PS to address this issue. We found a chimeric protein where C99 is fused to the PS1 N-terminus undergoes in cis processing to produce A[beta] and that a fusion protein harboring FAD-linked PS1 mutations overproduced A[beta]42. To change the molecular interactions within the C99-PS1 fusion protein, we made sequential deletions of the junction between C99 and PS1. We found differential effects of deletion in C99-PS1 on A[beta]40 and 42 production. Deletion of the junction between APP CTF and PS1 in the fusion protein decreased A[beta]40, while it did not decrease A[beta]42 production in the presence or absence of FAD-linked PS1 mutation. These results are consistent with the idea that the APP/PS interaction is differentially regulated during A[beta]40 and 42 production.