Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 53, Issue 6-8, Pages 263-269Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2008.08.004
Keywords
alpha-Synuclein; Amyloid beta; PC12 cells; Nitric oxide; Programmed cell death
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Funding
- Ministry of Science and Higher Education [2PO5A4129]
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alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part of Alzheimer's dementia related plaques. However, the role of alpha-synuclein in pathomechanism of Alzheimer's disease remains elusive. In particular, the relationship between alpha-synuclein and amyloid beta is unknown. In the present study we showed the involvement of alpha-synuclein in amyloid beta secretion and in the mechanism of amyloid beta evoked mitochondria dysfunction and cell death. Rat pheochromocytoma PC 12 cells transfected with amyloid beta precursor protein bearing Swedish double Mutation (APPsw) and control PC12 cells transfected with empty vector were used in this study. alpha-Synuclein (10 mu M) was found to increase by twofold amyloid beta secretion from control and APPsw PC12 cells. Moreover, alpha-synuclein decreased the viability of PC12 cells by about 50% and potentiated amyloid beta toxicity leading to mitochondrial dysfunction and caspase-dependent programmed cell death. Inhibitor of caspase-3 (Z-DEVD-FMK, 100 mu M), and a mitochondrial permeability transition pore blocker, cyclosporine A (2 mu M) protected PC12 cells against alpha-synuclein or amyloid beta evoked cell death. In contrast Z-DEVD-FMK and cyclosporine A were ineffective ill APPsw cells containing elevated amount of amyloid beta treated with alpha-synuclein. It was found that the inhibition of neuronal and inducible nitric oxide synthase reversed the toxic effect of alpha-synuclein in control but not in APPsw cells. Our results indicate that alpha-synuclein enhances the release and toxicity of amyloid beta leading to nitric oxide mediated irreversible mitochondria dysfunction and caspase-dependent programmed cell death. (C) 2008 Elsevier Ltd. All rights reserved.
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