APP is a transmembrane protein with the C-terminus of the Aβ region located within the intramembranous domain.22 Aβ is generated by the sequential cleavage of APP by a set of secretases. β-secretase cleaves APP at the N-terminus of the Aβ peptide, generating a C-terminal fragment that becomes the substrate for γ-secretase, which generates the Aβ C-terminus. By contrast, a third secretase, known as α-secretase, cleaves APP within the Aβ domain, precluding the generation of Aβ. Presenilins are best known for their role as part of the multiprotein complex known as γ-secretase, which executes the intramembranous cleavage of many transmembrane proteins, including APP.23 Presenilin FAD mutations cause APP processing to be shunted toward the longer, more amyloidogenic Aβ42 species23; an observation that can be been seen as supportive of the amyloid hypothesis.
