α-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells |
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| Institution: | 1. Cyprus University of Technology, Department of Agricultural Sciences, Biotechnology & Food Science, 3603, Lemesos, Cyprus;2. Institute of Plant Breeding and Genetic Resources, Department of Deciduous Fruit Trees, Hellenic Agricultural Organization ''Demeter'', 38 R.R. Station, 59035, Naoussa, Greece;3. Aristotle University of Thessaloniki, School of Agriculture, 54124, Thessaloniki, Greece;4. Alexander Technological Educational Institute, Department of Agricultural Technology, 57400, Sindos-Thessaloniki, Greece;5. Technological Educational Institute of Crete, Department of Agricultural Technology, 71004, Estavromenos, Heraklion, Crete, Greece;1. Biomolecular NMR Laboratory, Organic Chemistry Department, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain;2. Institute for Research in Biomedicine (IRB-Barcelona), Baldiri Reixac 10-12, 08028 Barcelona, Spain;3. Department of Physicochemistry, Faculty of Pharmacy, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain;4. Department of Physical Chemistry, Faculty of Chemistry, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain;1. College of Life Sciences, Liaoning Normal University, Dalian 116081, China;2. Department of Biotechnology, Dalian Medical University, Dalian 116044, China;1. Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA 30341, USA;2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, CT 06103, USA;1. C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia |
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| Abstract: | α-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 α-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 α-synuclein in pathomechanism of Alzheimer’s disease remains elusive. In particular, the relationship between α-synuclein and amyloid beta is unknown. In the present study we showed the involvement of α-synuclein in amyloid beta secretion and in the mechanism of amyloid beta evoked mitochondria dysfunction and cell death. Rat pheochromocytoma PC12 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. α-Synuclein (10 μM) was found to increase by twofold amyloid beta secretion from control and APPsw PC12 cells. Moreover, α-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 μM), and a mitochondrial permeability transition pore blocker, cyclosporine A (2 μM) protected PC12 cells against α-synuclein or amyloid beta evoked cell death. In contrast Z-DEVD-FMK and cyclosporine A were ineffective in APPsw cells containing elevated amount of amyloid beta treated with α-synuclein. It was found that the inhibition of neuronal and inducible nitric oxide synthase reversed the toxic effect of α-synuclein in control but not in APPsw cells. Our results indicate that α-synuclein enhances the release and toxicity of amyloid beta leading to nitric oxide mediated irreversible mitochondria dysfunction and caspase-dependent programmed cell death. |
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