Highly purified. A 19 aa peptide within the c-terminus of human nicastrin (1). Beta-amyloid (Ab) deposition in the brain is the hallmark of Alzheimer's Disease (AD). To initiate Ab formation, b-secretase cleaves APP at the N-terminus of Ab to release APPsb (~100kD soluble NT-fragment), and C99, a 12-kD CT membrane fragment. Alternatively, a-secretase cleaves within the Ab to prevent the formation of Ab. Cleavage by a-secretase produces a soluble N-terminal fragment, APPsa, and a 10-kD membrane C-terminal fragment, C83. Both C99 and C83 can be further cleaved by g-secretase releasing Ab and a nonpathogenic p3 peptide, respectively. Both Presenilins and a newly discovered protein, Nicastrin are required for this activity. Nicastrin may act to position the APP stub correctly to allow presenilin to cut it at the right place; or it might regulate the activity of the g-secretase enzyme (possibly presenilin). Suppression of nicastrin expression in C. elegans embryos induces a subset of notch/