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Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1.

Publication ,  Journal Article
Ridnour, LA; Dhanapal, S; Hoos, M; Wilson, J; Lee, J; Cheng, RYS; Brueggemann, EE; Hines, HB; Wilcock, DM; Vitek, MP; Wink, DA; Colton, CA
Published in: J Neurochem
December 2012

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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Published In

J Neurochem

DOI

EISSN

1471-4159

Publication Date

December 2012

Volume

123

Issue

5

Start / End Page

736 / 749

Location

England

Related Subject Headings

  • Tissue Inhibitor of Metalloproteinase-1
  • Tandem Mass Spectrometry
  • Reverse Transcriptase Polymerase Chain Reaction
  • Nitric Oxide
  • Neurology & Neurosurgery
  • Mice, Transgenic
  • Mice
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 2
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Ridnour, L. A., Dhanapal, S., Hoos, M., Wilson, J., Lee, J., Cheng, R. Y. S., … Colton, C. A. (2012). Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem, 123(5), 736–749. https://doi.org/10.1111/jnc.12028
Ridnour, Lisa A., Sneha Dhanapal, Michael Hoos, Joan Wilson, Jennifer Lee, Robert Y. S. Cheng, Ernst E. Brueggemann, et al. “Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1.J Neurochem 123, no. 5 (December 2012): 736–49. https://doi.org/10.1111/jnc.12028.
Ridnour LA, Dhanapal S, Hoos M, Wilson J, Lee J, Cheng RYS, et al. Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem. 2012 Dec;123(5):736–49.
Ridnour, Lisa A., et al. “Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1.J Neurochem, vol. 123, no. 5, Dec. 2012, pp. 736–49. Pubmed, doi:10.1111/jnc.12028.
Ridnour LA, Dhanapal S, Hoos M, Wilson J, Lee J, Cheng RYS, Brueggemann EE, Hines HB, Wilcock DM, Vitek MP, Wink DA, Colton CA. Nitric oxide-mediated regulation of β-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem. 2012 Dec;123(5):736–749.
Journal cover image

Published In

J Neurochem

DOI

EISSN

1471-4159

Publication Date

December 2012

Volume

123

Issue

5

Start / End Page

736 / 749

Location

England

Related Subject Headings

  • Tissue Inhibitor of Metalloproteinase-1
  • Tandem Mass Spectrometry
  • Reverse Transcriptase Polymerase Chain Reaction
  • Nitric Oxide
  • Neurology & Neurosurgery
  • Mice, Transgenic
  • Mice
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 2
  • Male