A beta([25-35]) peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism: Involvement of H2O2, caspase-3, NF-kappa B, p53 and c-Jun

作者：Velez Pardo C^*; Ospina GG; del Rio MJ

来源：NeuroToxicology, 2002, 23(3): 351-365.

DOI：10.1016/S0161-813X(02)00081-5

• apoptosis
• amyloid-beta
• caspase
• lymphocytes
• stress
• transcription factors

The Abeta deposition in the neuritic plaques is one of the major neuropathological hallmarks of the Alzheimer disease (AD). Studies in vitro have demonstrated that the Abeta(25-35) fragment, which contains the cytotoxic functional sequence of the amyloid peptide, induces neurotoxicity and cell death by apoptosis. Despite intense investigations, a complete picture of the precise molecular cascade leading to cell death in a single cellular model is still lacking. In this study, we provide evidence that Abeta(25-35) induce apoptosis either alone or in presence of iron in peripheral blood lymphocytes cells (PBL) in a concentration-dependent fashion by an oxidative stress mechanism involving: (1) the production of hydrogen peroxide (H2O2), reflected by rhodamine-positive fluorescent cells, (2) activation and/or translocation of NF-kappaB, p53 and c-Jun transcription factors showed by immunocytochemical diaminobenzidine positive nuclei, (3) activation of NF-kappaB complex by electrophoretic mobility shift assay/immuno-blotting/and ammonium pyrrolidinedithiocarbamate (PDTC) inhibition, (4) caspase-3 activation, reflected by caspase Ac-DEVD-cho inhibition, (5) mRNA synthesis de novo according to actinomycin D cell death inhibition. These results are consistent with the notion that the Abeta(25-35)/H2O2 generation precede the apoptotic process and that once H2O2 is generated, it is able to trigger a specific cell death signalisation. Thus, taken together these results, we present a well-ordered cascade of the major molecular events leading PBL to apoptosis. These results may contribute to explain the importance of Abeta alone or in the presence of redox-available iron in association with Abeta plaques (and neurofibrillary tangles) in AD brains and the significant role played by H2O2 as a second messenger of death signal in some degenerative diseases linked to oxidative stress stimuli.

• 出版日期2002-9