Cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates the amino and carboxy termini, respectively, of the Aβ amyloidogenic peptides Aβ40 and Aβ42—the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of γ-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease^, increase the production of Aβ42 (refs ,,), the more amyloidogenic peptide; γ-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of γ-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a γ-secretase cofactor, or helps to colocalize γ-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent γ-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of γ-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen.