Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1.

Presenilin 1 (PS1) comprises a catalytic subunit of γ-secretase, which is an intramembrane-cleaving protease responsible for generation of amyloid-β peptides as well as Notch cleavage, the latter being implicated in cancer. We have shown that transmembrane domains (TMDs) 1, 6, 7, and 9 of PS1 form the "catalytic pore" structure within the membrane for intramembrane proteolysis. Here we report a novel monoclonal antibody 9D11, which directly recognizes the TMD1-proximal residues in the hydrophilic loop region. Intriguingly, 9D11 inhibited the γ-secretase activity irrespective of the binding of known γ-secretase inhibitors and abolished Notch signaling-dependent cancer cell viability. Our data suggest that the juxtamembrane region of TMD1 of PS1 is a novel molecular target for the mechanism-based inhibition of γ-secretase and the development of the anticancer drug.