Fibrillar amyloid plaques are largely composed of amyloid-beta (Ab) peptides that are metabolized into products, including Ab1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of Ab 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 Ab in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and Ab 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 Ab1-16 fragment, and used mass spectrometry multi-reaction monitoring assay for detection of immunoprecipitated Ab1-16 peptides. Ab1-16 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/NOS2À/À 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).
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