Figure 5. Aβ production in the regulated secretory pathway of neurons provides the majority of extracellular Aβ that causes memory loss.

Aβ peptides are generated by proteolytic processing of the amyloid precursor protein (APP) in secretory vesicles that undergo axonal transport from the neuronal cell body to nerve terminals, where Aβ is secreted. Secretory vesicles of the regulated secretory pathway (yellow circles) provide the majority of secreted, extracellular Aβ peptides [9, 10, 16, 74–76]. Some Aβ is also provided by the basal, constitutive secretory pathway (constitutive secretory vesicles shown as blue circles). Intracellular production of Aβ within secretory vesicles occurs by cleavage at the N-terminus of Aβ within APP, achieved by proteases known as β-secretases, and cleavage at the C-termini of Aβ within APP which is achieved by γ-secretases. Proteolytic processing by β- and γ-secretases results in Aβ peptides of 40 and 42 residues, known as Aβ(1–40) and Aβ(1–42). Extracellular Aβ peptides in brain accumulate as oligomers and aggregates in amyloid plaques, and cause loss of memory in Alzheimer’s disease.