| Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1. | |
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MedLine Citation:
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PMID: 23016931 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Fibrillar amyloid plaques are largely composed of amyloid-beta (Aβ) peptides that are metabolized into products, including Aβ1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of Aβ proteins is critical to amyloid accumulation and resulting disease. Regulation of MMP-9 and its endogenous inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 by nitric oxide (NO) has been shown. We hypothesize that nitric oxide synthase (NOS2) protects against Alzheimer's disease pathology by increasing amyloid clearance through NO regulation of MMP-9/TIMP-1 balance. We show NO-mediated increased MMP-9/TIMP-1 ratios enhanced the degradation of fibrillar Aβ in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and Aβ degradation was examined by comparing an Alzheimer's disease mouse model that expresses NOS2 with a model lacking NOS2. To quantitate MMP-9 mediated changes, we generated an antibody recognizing the Aβ1-16 fragment, and used mass spectrometry multi-reaction monitoring assay for detection of immunoprecipitated Aβ1-16 peptides. Aβ1-16 levels decreased in brain lysates lacking NOS2 when compared with strains that express human amyloid precursor protein on the NOS2 background. TIMP-1 increased in the APPSwDI/NOS2(-/-) mice with decreased MMP activity and increased amyloid burden, thereby supporting roles for NO in the regulation of MMP/TIMP balance and plaque clearance. |
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Authors:
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Lisa A Ridnour; Sneha Dhanapal; Michael Hoos; Joan Wilson; Jennifer Lee; Robert Y S Cheng; Ernst E Brueggemann; Harry B Hines; Donna M Wilcock; Michael P Vitek; David A Wink; Carol A Colton |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural Date: 2012-10-25 |
Journal Detail:
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Title: Journal of neurochemistry Volume: 123 ISSN: 1471-4159 ISO Abbreviation: J. Neurochem. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-11-08 Completed Date: 2013-01-10 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: England |
Other Details:
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Languages: eng Pagination: 736-49 Citation Subset: IM |
Copyright Information:
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Published 2012. This article is a US Government work and is in the public domain in the USA. |
Affiliation:
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Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 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* Amyloid beta-Peptides / metabolism* Animals Astrocytes / metabolism Brain / metabolism Chromatography, Liquid Disease Models, Animal Enzyme-Linked Immunosorbent Assay Female Humans Immunoprecipitation Male Matrix Metalloproteinase 2 / metabolism Matrix Metalloproteinase 9 / metabolism* Mice Mice, Transgenic Nitric Oxide / metabolism* Reverse Transcriptase Polymerase Chain Reaction Tandem Mass Spectrometry Tissue Inhibitor of Metalloproteinase-1 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AG031845/AG/NIA NIH HHS; R01 AG031124/AG/NIA NIH HHS; R01 AG031845/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Peptides; 0/Tissue Inhibitor of Metalloproteinase-1; 10102-43-9/Nitric Oxide; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.35/Matrix Metalloproteinase 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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