Amyloid-beta precursor protein (APP) is the source of the amyloid-beta (Ab) peptide found in neuritic plaques of Alzheimer’s disease (AD) patients. APP is aglycosylated transmembrane protein with a long extracellular N-terminal domain, a short intracellular C-terminal domain, and an Abeta-segment of intermediate length shared between the intra- and extracellular regions. APP is cleaved by alpha-secretase immediately before or after reaching the cell surface, releasing the nonamyloidogenic secreted form of the N-terminal soluble APP fragment (sAPPa). APP molecules that are not cleaved by alpha-secretase are internalized, and subjected to beta-site cleavage by beta-secretase, leaving behind a membrane-bound C-terminal stub. This terminal stub is the substrate for gamma-secretase, which cleaves the molecule at gamma-site(s) to release the 40aa, 42aa, or 43aa -long Ab peptides.