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γ-Secretase is a membrane protein complex with an unusual aspartyl protease activity that catalyses the regulated intramembranous cleavage of the β-amyloid precursor protein (APP) to release the Alzheimer's disease (AD)-associated amyloid β-peptide (Aβ) and the APP intra-cellular domain (AICD)[SUB1]. Here we show the reconstitution of γ-secretase activity in the yeast Saccharomyces cerevisiae, which lacks endogenous γ-secretase activity. Reconstituted γ-secretase activity depends on the presence of four complex components including presenilin (PS)[SUP1], nicastrin (Nct)[SUP2], APH-1 (refs 3-6) and PEN-2 (refs 4, 7), is associated with endoproteolysis of PS[SUP8], and produces Aβ and AICD in vitro. Thus, the biological activity of γ-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast. [ABSTRACT FROM AUTHOR]