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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • December 2012

Published In

Volume / Issue

  • 123 / 5

Start / End Page

  • 736 - 749

PubMed ID

  • 23016931

Pubmed Central ID

  • 23016931

Electronic International Standard Serial Number (EISSN)

  • 1471-4159

International Standard Serial Number (ISSN)

  • 0022-3042

Digital Object Identifier (DOI)

  • 10.1111/jnc.12028

Language

  • eng