Novel proline endopeptidase inhibitors do not modify Aβ40/42 formation and degradation by human cells expressing wild‐type and Swedish mutated β‐amyloid precursor protein

• Published in: British journal of pharmacology 2000-08, Vol.130 (7), p.1613-1617
• Main Authors: Petit, Agnès, Barelli, Hélène, Morain, Philippe, Checler, Frédéric
• Format: Article
• Language: English
• Subjects: Alzheimer' disease; Aβ degradation; Aβ secretion; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; HEK293 cells; inhibitors; Life Sciences; Medical sciences; Neurology; Proline endopeptidase; secretases; Swedish mutant βAPP; wild‐type βAPP
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703440

Previous studies have suggested that proline endopeptidase (PE) could participate to the catabolism of the β‐amyloid peptide (Aβ) or to the physiopathological maturation of the β‐amyloid protein precursor (βAPP). We have examined the putative ability of human purified PE to catabolize Aβ40 and Aβ42 and the possible contribution of this enzyme to the generation of Aβ40 and Aβ42 in human HEK293 cells. We show first that purified human PE does not degrade synthetic Aβ40 and Aβ42, in vitro. We establish that HEK293 cell homogenates exhibit a Z‐Gly‐Pro‐7AMC‐cleaving enzyme, the activity of which is inhibited by Z‐Pro‐Prolinal and S17092 and S19825, two novel PE inhibitors, with affinities similar to those displayed on the purified human PE. These inhibitors also penetrate cells and achieve a full inhibition of endogenous proline endopeptidase in human cells. By means of selective antibodies directed towards the C‐terminal of Aβ40 and Aβ42, we assessed the effect of PE inhibitors on the recovery of both Aβ species. This was examined in HEK293 cells stably overexpressing the wild‐type and the familial Alzheimer' disease‐related Swedish mutated β‐APP. We establish that none of these inhibitors affected Aβ40 or Aβ42 production in these transfected cells. Overall, our study indicates that human PE does not degrade Aβ40 and Aβ42. Furthermore, PE does not contribute to Aβ40 and Aβ42 formation in HEK293 cells. Therefore, PE does not appear to contribute to the Aβ‐related aetiology of Alzheimer' disease. British Journal of Pharmacology (2000) 130, 1613–1617; doi:10.1038/sj.bjp.0703440