The A4 amyloid peptide is deposited in Alzheimer's disease inside neurons as neurofibrillary tangles or extracellularly as vascular amyloid. The A4 peptide is cleaved off by an unidentified proteinase from a larger precursor protein (APP), which resembles a cell surface receptor. The proteinase, which cleaves off the membrane-spanning domain of APP, may be important in amyloid formation. To evaluate this, a model peptide substrate, succinyl- isoleucyl-alanine-methylcoumarinamide, which is homologous to the C-terminal portion of A4 peptide, was synthesized to screen the putative A4-generating proteinase. On chromatographie purification, it was found that two proteinases are involved in the hydrolysis of the peptide, the major one being identified as a prolyl endopeptidase. This evidence may facilitate elucidation of the mechanism of amyloid deposition in Alzheimer's disease.
