@article{0657fefebde7414db0081cf1d88bfdb1,
title = "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.",
keywords = "amyloid, immunity, matrix metalloproteinase-9 (MMP-9), microglia, nitric oxide (NOS2), tissue inhibitor of metalloproteinase-1 (TIMP-1)",
author = "Ridnour, {Lisa A.} and Sneha Dhanapal and Michael Hoos and Joan Wilson and Jennifer Lee and Cheng, {Robert Y.S.} and Brueggemann, {Ernst E.} and Hines, {Harry B.} and Wilcock, {Donna M.} and Vitek, {Michael P.} and Wink, {David A.} and Colton, {Carol A.}",
year = "2012",
month = dec,
doi = "10.1111/jnc.12028",
language = "English",
volume = "123",
pages = "736--749",
number = "5",
}