PEN2, in addition to presenilin, nicastrin, and APH-1 forms the y-secretase protein complex, a membrane-bound aspartyl protease that can cleave certain proteins at peptide bonds buried within the hydrophobic environment of the lipid bilayer. This cleavage is responsible for a key step in signaling from several cell-surface receptors and is thought to be required for the generation of the neurotoxic amyloid peptides that are central to the pathogenesis of Alzheimer’s disease. Like the tumor necrosis factor-a-converting enzyme (TACE) and the b-site cleavage enzyme (BACE) protease families, y-secretase will cleave the amyloid precursor protein (APP), but within the intramembrane region of APP, resulting in either the non-toxic p3 (from the a and y cleavage site) or the toxic Ab amyloid peptide (from the b and y cleavage site). It is thought that accumulation of the Ab peptide is the precursor to Alzheimer's disease.