Review Volume 2, Issue 9 pp 545—554

Figure 1. APP metabolism: schematic representation of the non-amyloidogenic and amyloidogenic pathway. Here the 770 residue APP processing is schematized, even if the 695 and 751 transmembrane forms of APP exist. In the non-amyloidogenic pathway, α-secretase cleaves APP in the extracellular domain and releases soluble APPα into the extracellular space. Following this cleavage, a second enzymatic product, the C-terminal fragment (αCTF or C83), which can be a substrate for ɣ-secretase, yields a non-amyloidogenic 3 kDa fragment known as p3. In the amyloidogenic pathway Aβ is formed following cleavage by β and ɣ secretases, respectively. The cleavage of APP at the residue 1 of Aβ sequence results in a truncated form of sAPP (sAPPβ) and in a C-terminal fragment of 12 kDa (βCTF or C99). The final step in the amyloidogenic pathway is the cleavage of βCTF, to liberate Aβ by ɣ-secretase. Furthermore, in both the amyloidogenic and non-amyloidogenic pathways, the cleavage of C83 and C99 fragments by ɣ-secretase also results in the generation of C-terminal peptides of 57-58 residues, referred as APP intracellular domain (AICD).