Schematic representation of APP processing. APP is a type I transmembrane protein that can undergo two separate proteolytic pathways. In the non-amyloidogenic pathway, APP is processed by an α-secretase that clips within the Aβ region (thus precluding its formation), resulting in the release of a soluble ~110–120 kDa N-terminal APP fragment (sAPPα). This pathway also releases a CTF that is 83 amino acids in length (C83). C83 can also be cleaved by a γ-secretase to release a small, non-toxic 3 kDa fragment known as p3 and a γCTF known as APP intracellular domain (AICD). In the amyloidogenic pathway, APP is cleaved first by β-secretase releasing a sAPPβ fragment and leaving a 99 amino acid CTF attached to the membrane (C99). C99 is subsequently cleaved by a γ-secretase, within its intramembrane region to release the Aβ peptide and AICD. SP, Signal Peptide; KPI, Kunitz-type Proteinase Inhibitor domain.