Schematic drawing of APP and generation of Aβ isoforms. The 17-amino acid signal peptide is indicated at the N-terminus. A single membrane-spanning domain is located at amino acids 700-723 in the longest APP isoform (APP770). (a) In the amyloidogenic pathway, β-secretase cleaves after residue 671, generating β-sAPP, which is secreted, and a C-terminal fragment (β-CTF or C99), which is retained in the membrane. The β-CTF fragment can undergo further cleavage by γ-secretase to release Aβ isoforms. (b) In another pathway, APP is first cleaved by β-secretase, but after this, by α-secretase, thus generating the shorter isoforms Aβ1-14, Aβ1-15, and Aβ-16. In another described nonamyloidogenic pathway, α-secretase cleaves between amino acids 16 and 17 in the Aβ sequence generating α-sAPP, followed by γ-secretase cleavages, generating a fragment called p3 (Aβ17-40/42). This 3-kDa fragment has been isolated from cell-culture medium  and in brains from AD patients . However, the fragment has never been detected in human CSF. AICD, APP intracellular domain; APP, amyloid precursor protein; Aβ, amyloid β; sAPP, soluble amyloid precursor protein.