Document Detail


alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells.
MedLine Citation:
PMID:  18804502     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Anna Kazmierczak; Joanna B Strosznajder; Agata Adamczyk
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-08-29
Journal Detail:
Title:  Neurochemistry international     Volume:  53     ISSN:  0197-0186     ISO Abbreviation:  Neurochem. Int.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-25     Completed Date:  2009-03-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8006959     Medline TA:  Neurochem Int     Country:  England    
Other Details:
Languages:  eng     Pagination:  263-9     Citation Subset:  IM    
Affiliation:
Medical Research Center, Polish Academy of Sciences, Department of Cellular Signaling, Pawińskiego 5 str., 02-106 Warsaw, Poland. aniakazmierczak@gmail.com
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / 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:
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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