Amyloid precursor protein (APP) gene encodes multiple APPs ranging from 695 to 770 amino acids. The unprocessed form of APP is a putative cell surface receptor that possesses neurite-promoting activity, and is involved in synaptic vesicle recycling. Processing of APP by sequential enzymatic activity of β- and γ-secretase, and the presenilin proteins PS1 and PS2, produces APP fragments that may have unique functions. β-secretase activity cleaves the extracellular portion of APP leading to asecreted APP form, while γ-secretase activity produces β-Amyloid peptide (39-43 amino acids). The Aβ peptide produces abnormal plaques in the cerebral cortex and blood vesselwalls during Alzheimer's disease. Nicastrin is a PS1 associated transmembrane protein,that contains N-terminal glycosylation and myristoylation sites. Nicastrin can bind full length APP and the fragments produced by γ-secretase. In C. elegans, suppression of nicastrin expression produces phenotypes that mimic those produced when notch signaling proteins are suppressed. In Drosophila, deficiencies in nicastrin prevent cleavage of the intracellular portion of Notch. Thus, nicastrin may be a functional component of presenilins and γ-secretase complexes, which process Notch and APP transmembrane receptors.