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

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.

• 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
• Journal: Journal of neurochemistry (J Neurochem) Vol. 123 Issue 5 Pg. 736-49 (Dec 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 23016931 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Published 2012. This article is a US Government work and is in the public domain in the USA.

Chemical References

• Amyloid beta-Peptides
• Tissue Inhibitor of Metalloproteinase-1
• Nitric Oxide
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• 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)