| alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells. | |
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MedLine Citation:
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PMID: 18804502 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 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. alpha-Synuclein (10microM) 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, 100microM), and a mitochondrial permeability transition pore blocker, cyclosporine A (2microM) protected PC12 cells against alpha-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 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. |
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Authors:
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Anna Kazmierczak; Joanna B Strosznajder; Agata Adamczyk |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-08-29 |
Journal Detail:
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Title: Neurochemistry international Volume: 53 ISSN: 0197-0186 ISO Abbreviation: Neurochem. Int. Publication Date: 2008 Dec |
Date Detail:
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Created Date: 2008-11-25 Completed Date: 2009-03-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8006959 Medline TA: Neurochem Int Country: England |
Other Details:
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Languages: eng Pagination: 263-9 Citation Subset: IM |
Affiliation:
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Medical Research Center, Polish Academy of Sciences, Department of Cellular Signaling, Pawińskiego 5 str., 02-106 Warsaw, Poland. aniakazmierczak@gmail.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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metabolism*,
physiopathology Amyloid beta-Protein / agonists, secretion*, toxicity Amyloid beta-Protein Precursor / genetics Animals Apoptosis / drug effects, physiology Bodily Secretions / drug effects, physiology Brain / metabolism*, physiopathology Cell Survival / drug effects, physiology Drug Synergism Enzyme Inhibitors / pharmacology Neurons / drug effects, metabolism*, secretion Nitric Oxide / metabolism Nitric Oxide Synthase Type I / drug effects, metabolism PC12 Cells Rats Transfection Up-Regulation / drug effects, physiology alpha-Synuclein / metabolism*, toxicity |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Amyloid beta-Protein Precursor; 0/Enzyme Inhibitors; 0/alpha-Synuclein; 10102-43-9/Nitric Oxide; EC 1.14.13.39/Nitric Oxide Synthase Type I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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