Fig. 1: The correspondence between APP cleavage pathways and proteolytic fragments with shared amino acid sequences.

A Flow chart showing three of the many possible cleavage pathways for the amyloid precursor protein (APP) and their associated fragments. The α- Aβ’- and β- cleavage pathways converge on γ- cleavage. CTF carboxy terminal fragment remaining in the membrane after initial cleavages, PS presenilins as part of the γ-secretase complex, AICD APP intracellular domain. P3, Aβ’ and Aβ represent the variable length peptides released following γ-cleavage. In the constitutive α-pathway APP is cleaved by a number of enzymes to release a large extracellular protein called soluble amyloid precursor protein α (sAPPα) leaving a membrane bound fragment that can be further processed by γ-cleavage, involving the presenilins, to P3, corresponding to Aβ from amino acid ~17. In the Aβ’ pathway, APP is first cleaved by an enzyme called BACE2 to release the large extracellular sAPPβ’ and a smaller Aβ’ fragment corresponding to Aβ from amino acid 11, In the β-pathway, APP is cleaved by an enzyme called BACE1 to release a large extracellular protein sAPPβ that is ~17 amino acids shorter than sAPPα, leaving a membrane bound fragment that can be further cleaved by the γ-secretase to release Aβ that is ~17 amino acids longer than P3. B Diagram showing the substantial sequence homology between the peptide fragments derived from the APP proteolytic system shown in Fig. 1A; fragment lengths are not to scale.