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

作者：Ridnour Lisa A; Dhanapal Sneha; Hoos Michael; Wilson Joan; Lee Jennifer; Cheng Robert Y S; Brueggemann Ernst E; Hines Harry B; Wilcock Donna M; Vitek Michael P; Wink David A; Colton Carol A^*

来源：Journal of Neurochemistry, 2012, 123(5): 736-749.

DOI：10.1111/jnc.12028

• amyloid
• immunity
• matrix metalloproteinase-9 (MMP-9)
• microglia
• nitric oxide (NOS2)
• tissue inhibitor of metalloproteinase-1 (TIMP-1)

Fibrillar amyloid plaques are largely composed of amyloid-beta (A beta) peptides that are metabolized into products, including A beta 1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of A beta 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 A beta in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and A beta 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 A beta 1-16 fragment, and used mass spectrometry multi-reaction monitoring assay for detection of immunoprecipitated A beta 1-16 peptides. A beta 1-16 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.

• 出版日期2012-12