Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Journal of neurochemistry, 2012-12, Vol.123 (5), p.736-749

Ort / Verlag

Oxford: Blackwell Publishing Ltd

Erscheinungsjahr

2012

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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. Nitric Oxide‐Mediated Regulation of β‐Amyloid Clearance via Alterations of MMP‐9/TIMP‐1 The balance between production and degradation of Abeta proteins is critical to amyloid accumulation and ensuing disease. Fibrillar Abeta is digested to less toxic products by proteolytic enzymes including MMP‐9. Our in vitro and in vivo data show that nitric oxide regulates both MMP‐9 and its endogenous inhibitor TIMP‐1. Thus Abeta degradation and clearance are controlled by MMP9/TIMP1 ratio in an NO‐dependent manner.