SECRETASE, ALZHEIMER AMYLOID PROTEIN-PRECURSOR SECRETING ENZYME IS NOT SEQUENCE-SPECIFIC

The major pathological change in Alzheimer's disease is the deposition of amyloid β A4-protein (βP) in the brain. βP is derived from a small part of the much larger amyloid protein precursor (APP). In the normal condition, APP is cleaved in the interior of βP, preventing the formation of βP, by a hypothetical proteinase "secretase". To characterize this enzyme, APP and mutated APPs were expressed by cDNA transfection in COS-1 cells, a monkey kidney fibroblast derived cell line. The mutant APPs with the mutations of the proposed cleavage site (Gln686-Lys687) were processed in the same way as wild APP. The deleted mutant APP (deletion of Arg676-Asp694) was also cleaved in a similar way to wild APP. The cleavage site of this deletion mutant was located at the 12 amino acid residues from the predicted membrane spanning domain. Hence, "secretase" cleaves APP, depending not on its specific amino acid sequence, but probably on the relative conformation with plasma membrane. © 1991.