Familial Alzheimer disease-linked presenilin 1 variants enhance production of both Aβ1-40 and Aβ1-42 peptides that are only partially sensitive to a potent aspartyl protease transition state inhibitor of "γ-secretase"

Presenilin 1 (PS1) plays an essential role in intramembranous "γ-secretase" processing of several type I membrane proteins, including the β-amyloid precursor proteins (APP) and Notch1. In this report, we examine the activity of two familial Alzheimer's disease-linked PS1 variants on the production of secreted Aβ peptides and the effects of L-685,458, a potent γ-secretase inhibitor, on inhibition of Aβ peptides from cells expressing these PS1 variants. We now report that PS1 variants enhance the production and secretion of both Aβ1-42 and Aβ1-40 peptides. More surprisingly, whereas the IC₅₀ for inhibition of Aβ1-40 peptide production from cells expressing wild-type PS1 is ∼1.5 μM, cells expressing the PS1ΔE9 mutant PS1 exhibit an IC₅₀ of ∼4 μM. Immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry reveal that the levels of Aβ1-43 peptides are elevated in medium of PS1ΔE9 cells treated with higher concentrations of inhibitor. The differential effects of wild-type and mutant PS1 on γ-secretase production of Aβ peptides and the disparity in sensitivity of these peptides to a potent γ-secretase suggest that PS may be necessary, but not sufficient, to catalyze hydrolysis at the scissile bonds that generate the termini of Aβ1-40 and Aβ1-42 peptides.