Inhibition of prolylendopeptidase does not affect γ-secretase processing of amyloid precursor protein in a human neuroblastoma cell line

Abeta peptides are major components of the amyloid plaques that characterize Alzheimer's disease. The enzyme activities (beta- and gamma-secretases) involved in generating Abeta from amyloid precursor protein (APP) are unidentified. It has been suggested that prolylendopeptidase (PEP), an oligopeptidase that normally cleaves after proline residues, could also cleave after the alanine at position 42 of Abeta to generate Abeta42. We investigated whether inhibition of PEP activity in human neuroblastoma cells affected Abeta levels in cell culture media. An SH-SY5Y cell line expressing SPA4CT, encoding the C-terminal 100 residues of APP and the signal sequence, was used. Only gamma-secretase activity is required for Abeta production in this cell line. The PEP inhibitor Fmoc-AlaPro-CN (10 microM) reduced PEP activity in these cells…