The Presenilin 1 (PS1) and Presenilin 2 (PS2) transmembrane proteins are components of high molecular weight complexes. These complexes mediate proteolytic cleavage within the transmembrane domain of several proteins, including the ∫-Amyloid precursor protein (∫APP) and Notch. Missense mutations in the genes encoding the Presenilin proteins increase the proteolysis of ∫APP and results in the overproduction of the neurotoxic ∫-Amyloid peptide, which results in a condition associated with Familial Alzheimer’s disease (FAD). A novel component of the presenilin complex, nicastrin, is a type I transmembrane glycoprotein that is involved in mediating Notch/GLP-1 signaling. In addition, nicastrin contributes to the processing of ∫APP, which makes nicastrin an attractive potential target for modulating the production of ∫-Amyloid in patients with Alzheimer’s disease. Originally purified from immunoprecipitated PS1 complexes from HEK293 cells, nicastrin contains hydrophilic amino and carboxy-terminal domains, a short, hydrophobic transmembrane domain and potential N-myristoylation and phosphorylation sites.