| Autor: |
Medvedev AE; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.; Institute of Biomedical Chemistry, Moscow, Russia., Radko SP; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.; Institute of Biomedical Chemistry, Moscow, Russia., Yurinskaya MM; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.; Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia., Vinokurov MG; Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia., Buneeva OA; Institute of Biomedical Chemistry, Moscow, Russia., Kopylov AT; Institute of Biomedical Chemistry, Moscow, Russia., Kozin SA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Mitkevich VA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Makarov AA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. |
| Abstrakt: |
Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-β(Aβ) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aβ42 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 (Aβ1-5) from synthetic Aβ peptide analogues. In the context of proteolytic processing of full length Aβ42, this suggests possible formation of Aβ6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aβ peptide(s) could retain aggregability and neurotoxic properties typical for Aβ42. We have investigated aggregability of two amyloid-β peptides, Aβ6-42 and isoD7-Aβ6-42, mimicking potential proteolytic products of Aβ42 and isoD7-Aβ42, and evaluated their effects on the repertoire of brain Aβ binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aβ6-42 and Aβ6-42 was higher than that of full-length peptides Aβ42 and isoD7-Aβ42, while the repertoire of mouse brain Aβ binding proteins dramatically decreased. Aβ6-42 and isoD7-Aβ6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aβ42 and isoD7-Aβ42, 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 Aβs could result in formation of more pathogenic peptides. |
