The ultimate step in Alzheimer’s disease Abgeneration involves c-secretase, which releases Abfrom its membrane-bound precursor. Asimilar presenilin-dependent proteolytic activity is implicated in the release of theNotch intracellular domain. We have developed a novel assay forc-secretase activity based on green fluorescent protein detection. This involves cotransfection of a substrate-activator based on the amyloid precursor protein or the Notch sequence and a fluorescent reporter gene.