The third proteolytic cleavage releases the Notch IntraCellular Domain (NICD) from the NEXT fragment. The catalyst for this cleavage is a membrane protease complex called gamma-secretase (GS). GS cleaves type I membrane proteins such as the Notch receptor and amyloid beta-protein precursor (APP, implicated in Alzheimer's disease). GS is made up of 4 components: Presenilin, nicastrin, APH-1 and PEN-2. Presenilins are homodimeric, multipass transmembrane proteins and are believed to be the catalytic core of GS. All aspartyl proteases have two catalytic aspartates and presenilin contains these residues. The others are essential cofactors for the correct function of GS.