SOUTH SAN FRANCISCO—Production and deposition of amyloid β (Aβ) is one of the key steps in the initial pathogenesis of Alzheimer's disease. Unfortunately, an enzyme involved in Aβ formation, γ-secretase, is also involved in other critical signaling pathways, so efforts to stop Aβ formation with γ-secretase inhibitors are complicated by significant toxicity issues. Recently, researchers at Elan Pharmaceuticals looked at presenilins PS1 and PS2, constituents of the γ-secretase complex, to see if it might be possible to specifically inhibit Aβ formation without perturbing other signaling functions.
In the Journal of Biological Chemistry, the researchers describe the production of PS1-/-/PS2-/- knockout fibroblast cell lines they transfected with either PS1 or PS2 to selectively reconstitute the γ-secretase complex. They then probed these cells with different γ-secretase inhibitors to see if any of the compounds were selective for PS1 or PS2. Of the different inhibitor classes tested, the researchers noted the sulfonamides showed preferential inhibition of PS1-γ-secretase, including compounds from Elan and BMS.
Using chimeric PS1/PS2 genes and performing alanine scan mutagenesis to identify what residues in PS1 were necessary and responsible for the sulfonamide preference, the researchers honed in on three amino acids in PS1. When coupled with research suggesting that ablation of different γ-secretase subunits exhibits different impacts on other signaling pathways, the new findings suggest that isoform-selective inhibitors may offer an option for γ-secretase inhibition that only targets Aβ production.