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

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

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)736-749
Number of pages14
JournalJournal of Neurochemistry
Volume123
Issue number5
DOIs
StatePublished - Dec 2012

Keywords

  • amyloid
  • immunity
  • matrix metalloproteinase-9 (MMP-9)
  • microglia
  • nitric oxide (NOS2)
  • tissue inhibitor of metalloproteinase-1 (TIMP-1)

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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