RESUMO
Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-ß(Aß) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aß42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aß1-5) from synthetic Aß peptide analogues. In the context of proteolytic processing of full length Aß42, this suggests possible formation of Aß6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aß peptide(s) could retain aggregability and neurotoxic properties typical for Aß42. We have investigated aggregability of two amyloid-ß peptides, Aß6-42 and isoD7-Aß6-42, mimicking potential proteolytic products of Aß42 and isoD7-Aß42, and evaluated their effects on the repertoire of brain Aß binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aß6-42 and Aß6-42 was higher than that of full-length peptides Aß42 and isoD7-Aß42, while the repertoire of mouse brain Aß binding proteins dramatically decreased. Aß6-42 and isoD7-Aß6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aß42 and isoD7-Aß42, respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aßs could result in formation of more pathogenic peptides.
