Identification of a putative amyloid A4‐generating enzyme as a prolyl endopeptidase

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.