| First Author | Ridnour LA | Year | 2012 |
| Journal | J Neurochem | Volume | 123 |
| Issue | 5 | Pages | 736-49 |
| PubMed ID | 23016931 | Mgi Jnum | J:190735 |
| Mgi Id | MGI:5449637 | Doi | 10.1111/jnc.12028 |
| Citation | Ridnour LA, et al. (2012) Nitric oxide-mediated regulation of beta-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem 123(5):736-49 |
| abstractText | Fibrillar amyloid plaques are largely composed of amyloid-beta (Abeta) peptides that are metabolized into products, including Abeta1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of Abeta 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 Abeta in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and Abeta 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 Abeta1-16 fragment, and used mass spectrometry multi-reaction monitoring assay for detection of immunoprecipitated Abeta1-16 peptides. Abeta1-16 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. |
