Fig. 1

A simplified scheme of APP proteolytic processing and the origin of Aβ plaques. APP is a type I transmembrane receptor that contains Aβ peptide within its sequence. α-secretases such as ADAM10/17 cleave APP inside the Aβ peptide, which is disrupting, and produces soluble, secreted sAPPα fragment. sAPPα is neuroprotective, and thus this cleavage is called non-amyloidogenic pathway. The C83 peptide can be further cleaved by γ-secretase producing soluble P3 peptide. In contrast, APP can be cleaved by β-secretase, for example BACE1, creating a cytotoxic, soluble sAPPβ. The proteolysis by β-secretase exposes Aβ peptide, which is further cleaved by γ-secretase. This cleavage results in the release of Aβ monomers into the extracellular space, where they can further polymerize forming Aβ oligomers, and later Aβ plaques. This pathway is neurotoxic and is called amyloidogenic pathway