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Nitric oxide‐mediated regulation of β ‐amyloid clearance via alterations of MMP ‐9/ TIMP ‐1
Author(s) -
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.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12028
Subject(s) - nitric oxide , matrix metalloproteinase , nitric oxide synthase , chemistry , amyloid precursor protein , proteases , amyloid (mycology) , in vivo , endogeny , alzheimer's disease , biochemistry , endocrinology , medicine , enzyme , biology , disease , inorganic chemistry , microbiology and biotechnology , organic chemistry
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 ( NOS 2) 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 NOS 2 with a model lacking NOS 2. 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 NOS 2 when compared with strains that express human amyloid precursor protein on the NOS 2 background. TIMP ‐1 increased in the APPS w DI / NOS 2 −/− mice with decreased MMP activity and increased amyloid burden, thereby supporting roles for NO in the regulation of MMP / TIMP balance and plaque clearance.