Abstract
The last data indicated that about 60% of sporadic and familial Alzheimer Disease (AD) patients contain in the brain Levy bodies in which ASN is fundamental component. However, the role of ASN in AB toxicity and in pathomechanism of AD is unknown. The relationship between ASN, its neurotoxic fragment, peptide NAC and AB remains unclear. The aim of our study was to analyzed the involvement of ASN in AB peptide secretion and in mechanism of AB evoked mitochondria dysfunction and cell death. Rat pheochromocytoma PC12 cells transfected with AB precursor protein bearing Swedish double mutation (APPsw) and control PC12 cells transfected with empty vector were used in this study. Our data showed that non aggregated ASN(10uM) induced 2-fold increase of AB secretion from control and APPsw PC12 cells. Moreover, ASN and NAC peptide (10uM) decreased viability of PC12 cells by about 50 and 70% respectively and potentiated AB induced apoptosis by enhancement of caspase 3 activity .Inhibitor of caspase-3 (Z-DEVD-FMK 100uM) and mitochondrial permeability transition pore blocker, cyclosporine A (2uM) protected PC12 and APPsw transfected cells against ASN and AB evoked cells death. These inhibitors had no effect when APPsw cell were additionally treated with ASN. Then the role of nitric oxide (NO) in mechanism of ASN and AB toxicity was indicated using specific inhibitors of different isoforms of NO synthases. Our data presented ameliorating effect of neuronal and inducible NOS inhibitors on ASN induced PC12 cells death and the lack of such a effect in APPsw cells treated with ASN where AB itself significantly activates nitrogenic stress. Our results indicate that ASN enhanced the release and toxicity of AB peptides leading to NO mediated irreversible mitochondria dysfunction and caspase dependent apoptotic cells death. Supported by: MS&HE grant 2PO5A 04129 and MS&HE scientific network No 28/E-32/SN-0053/2007
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