The presenilin proteins are required for intramembrane cleavage of a subset of type 1 membrane proteins including the Alzheimer’s disease amyloid precursor protein. Previous studies indicate presenilin proteins form enzymatically act-ive high molecular mass complexes consisting of hetero-dimers of N- and C-terminal fragments in association with nicastrin, presenilin enhancer-2 and anterior pharynx defective-1 proteins.