Distinct Intramembrane Cleavage of the β-Amyloid Precursor Protein Family Resembling γ-Secretase-like Cleavage of Notch*

The intramembrane cleavage of β-amyloid precursor protein by γ-secretase is the final step in the generation of amyloid β-protein. A 59- or 57-residue C-terminal fragment called CTFγ is produced concomitantly. Putative CTFγ generated in rat brain membrane preparations was purified and sequenced. Instead of CTFγ, shorter 50- and 49-residue fragments were identified. In addition, we found similar C-terminal fragments of β-amyloid precursor-like proteins 1 and 2; these were also cleaved at corresponding sites. This newly identified cleavage occurs at a site two to five residues inside the cytoplasmic membrane boundary, which is very similar to γ-secretase-like cleavage of Notch 1.