The regulated intramembrane proteolysis of the amyloid precursor protein (APP) that results in the generation of a toxic 40 to 42 amino acid fragment, Abeta, and a C-terminal intracellular fragment stands central in the pathogenesis of Alzheimer's disease. The fibrillar Abeta peptide is extracellularly deposited in plaques in the amygdala, the hippocampus, and the neocortex of affected individuals. The APP intracellular fragment binds to transcription factors and is translocated to the nucleus, where it influences transcription. Regulated intramembrane proteolysis of APP is dependent on the activity of a multimeric protein complex of which the essential components are presenilin, nicastrin, PEN-2, and APH-1. Further research into this emerging field of presenilin-dependent APP proteolysis within the plane of the membrane might reveal the necessity of an additional transport step-bringing substrate and enzyme together-before APP can actually be processed.