| Alterations in muscarinic receptor-coupled phosphoinositide hydrolysis and AP-1 activation in Alzheimer's disease cybrid cells. | |
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MedLine Citation:
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PMID: 10794846 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Alzheimer's disease cybrid cells produced by replacing endogenous mitochondria in human neuroblastoma SH-SY5Y cells with platelet mitochondria from subjects with Alzheimer's disease have higher levels of reactive oxygen species than do cybrid cells with mitochondria from control subjects. These cells were used to test if this chronic mild increase in reactive oxygen species affects muscarinic receptor-coupled signaling activities. Basal and carbachol-stimulated phosphoinositide hydrolysis were higher, and there was less inhibition by glutathione depletion, in Alzheimer's disease than control cybrid cells. Elevated phosphoinositide hydrolysis in Alzheimer's disease cybrid cells also was evident upon direct activation of G-proteins (Gq/11) linked to phosphoinositide signaling or of phospholipase C, but immunoblot analyses revealed equivalent levels of Gq/11 and phospholipase C in both cell lines. These results indicate that there is up-regulation of phosphoinositide signaling in Alzheimer's disease cybrid cells in association with chronic mild oxidative stress, although treatment of cells with H(2)O(2) to induce greater acute oxidative stress caused decreases in carbachol-stimulated phosphoinositide hydrolysis that were similar in Alzheimer's disease and control cybrid cells. In contrast to phosphoinositide hydrolysis, carbachol-stimulated AP-1 DNA binding activity was lower in Alzheimer's disease than control cybrid cells, and this deficit was associated with deficient protein kinase C-mediated activation of AP-1. Overall, these results demonstrate that chronically elevated reactive oxygen species in Alzheimer's disease cybrid cells are associated with a more robust phosphoinositide signaling system, but lower signaling to activation of AP-1. These alterations may represent adaptations to exposure to oxidants, which precede more widespread deficits in signaling associated with more severe oxidative stress. |
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Authors:
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P De Sarno; G N Bijur; R Lu; R E Davis; R S Jope |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Neurobiology of aging Volume: 21 ISSN: 0197-4580 ISO Abbreviation: Neurobiol. Aging Publication Date: 2000 Jan-Feb |
Date Detail:
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Created Date: 2000-07-07 Completed Date: 2000-07-07 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8100437 Medline TA: Neurobiol Aging Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 31-8 Citation Subset: IM |
Affiliation:
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Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, Birmingham, AL 35294-0017, USA. |
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*,
pathology Buthionine Sulfoximine / pharmacology Carbachol / pharmacology Cells, Cultured Cholinergic Agonists / pharmacology DNA / metabolism Enzyme Inhibitors / pharmacology GTP-Binding Proteins / metabolism Glutathione / metabolism Humans Hybrid Cells / cytology, metabolism* Hydrogen Peroxide / pharmacology Hydrolysis / drug effects Mitochondria / metabolism, transplantation Oxidative Stress / drug effects Phosphatidylinositols / metabolism* Protein Kinase C / metabolism Reactive Oxygen Species / metabolism Receptors, Muscarinic / metabolism* Signal Transduction / drug effects Transcription Factor AP-1 / metabolism* Type C Phospholipases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AG06569/AG/NIA NIH HHS; NS10795/NS/NINDS NIH HHS; NS37768/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cholinergic Agonists; 0/Enzyme Inhibitors; 0/Phosphatidylinositols; 0/Reactive Oxygen Species; 0/Receptors, Muscarinic; 0/Transcription Factor AP-1; 5072-26-4/Buthionine Sulfoximine; 51-83-2/Carbachol; 70-18-8/Glutathione; 7722-84-1/Hydrogen Peroxide; 9007-49-2/DNA; EC 2.7.11.13/Protein Kinase C; EC 3.1.4.-/Type C Phospholipases; EC 3.6.1.-/GTP-Binding Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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