Fig. 2: The APP matrix approach.

Adapted from [87]: Green: N-terminal fragments, blue: Aβ and P3 type fragments, purple: other fragments, grey: regulatory factors and processes. 1. Full length APP expression is likely rate limiting both for full length APP functional interactions and APP cleavages; factors that regulate APP expression and trafficking to particular cellular compartments may involve multiple cellular systems. 2. Factors that regulate the likelihood of the various APP cleavages, e.g. phosphorylation of threonine APP668 in the intracellular domain [125] may involve multiple cellular systems. 3. α-cleavage, involving the A Disintegrin And Metalloproteinase (ADAM)s 10, 17 and 9 [126], generates sAPPα and the carboxy terminal fragment (CTF) C83 and is considered to be constitutive and in contrast to β-cleavage appears to include redundancy of multiple enzymes. 4. β-cleavage involving BACE1 generates sAPPβ and the CTF C99 [127]; competitive inhibition arising from other substrates of BACE1 [128] requires clarification. 5. Other cleavages, e.g. by BACE2 [129] and the N-terminal eta-cleavage [130], have been omitted here for clarity but must be included in the full APP matrix approach. 6. Factors regulating processing of particular CTFs in specific cellular compartments require further clarification. 7. Factors regulating the expression, trafficking and functions of PSs [131] either dependent or independent from the γ-secretase complex [132] and competitive inhibition between different γ-secretase substrates e.g. Notch 1 [133] require clarification; while proteolysis of the CTFs C83 and C99 by γ-secretase may be differently affected by γ-secretase inhibitors [134] the relative affinities of γ-secretase with all CTFs have not been fully described. 8. Multiple molecular forms (amino acid sequences, post-translational modifications and aggregation states) have been collapsed into a single node for both Aβ and P3 for clarity but would be required in the full APP matrix. Further processing pathways e.g. via BACE2 [129] and catabolism of fragments e.g. Aβ [135] and CTFs [136] have also been omitted for clarity.