Document Detail


Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1.
MedLine Citation:
PMID:  23016931     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-10-25
Journal Detail:
Title:  Journal of neurochemistry     Volume:  123     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-08     Completed Date:  2013-01-10     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  736-49     Citation Subset:  IM    
Copyright Information:
Published 2012. This article is a US Government work and is in the public domain in the USA.
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / 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:
AG031845/AG/NIA NIH HHS; R01 AG031124/AG/NIA NIH HHS; R01 AG031845/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Tissue Inhibitor of Metalloproteinase-1; 31C4KY9ESH/Nitric Oxide; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.35/Matrix Metalloproteinase 9
Comments/Corrections

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