Cleavage of APP and Physiological roles of APP and APP Fragments. Amyloid precursor protein (APP) can be cleaved via two mutually exclusive pathways. Importantly, various studies have suggested that these various fragments of APP processing, including Aβ, can have a number of possible roles in normal brain physiology, shown in the boxes. In the so-called amyloidogenic pathway APP is cleaved by β-secretase (beta-site APP cleaving enzyme 1 (BACE1)) and β-secretase enzymes (PSEN1 is the catalytic core of the multiprotein γ-secretase complex). The initial β-secretase cleavage produces a large soluble extracellular domain, secreted amyloid precursor protein-β (sAPPβ). The remaining membrane bound C99 stud is then cleaved by multiple sequential γ-secretase cleavages. These begin near the inner membrane at a γ-secretase cleavage site epsilion (the ε-site) to produce the APP intracellular domain (AICD), and then subsequent sequential γ-secretase cleavages trim the remaining membrane bound component to produce different length Aβ peptides including Aβ43, Aβ42, Aβ40 and Aβ38 . In the so-called non-amyloidogenic pathway APP is processed consecutively by α- and γ-secretases to produce secreted amyloid precursor protein α (sAPPα), p3 (which is in effect Aβ17-40/42) and AICD. The major α-secretase enzyme is A Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). Cleavage via amyloidogenic and non-amyloidogenic pathways depends on the cellular localisation of cleavage enzymes, and of full-length APP, which are expressed and trafficked in specific sub-cellular locations.