APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity

Abstract A major component of the amyloid plaque core in Alzheimer’s disease (AD) is the 40–42-residue amyloid β peptide (Aβ). Mutations linked to AD such as those in presenilins 1 (PS1) and 2 (PS2) invariably increase the longer Aβ42 species that forms neurotoxic oligomers. It is believed that PS1/2 constitute the catalytic subunit of the γ-secretase responsible for the final step in Aβ biogenesis. Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the γ-secretase complex with PS1. Further, knockout studies using RNAi showed that these components are essential for γ-secretase activity. However, the nature of γ-secretase and how the aforementioned proteins regulate its activity are still incompletely understood. Here we present evidence that unlike PS1, overexpression of these proteins can increase the levels of Aβ, suggesting that these proteins are limiting for γ-secretase activity. In addition, our studies also suggest that the presenilin partners regulate the relative levels of Aβ40 and Aβ42.