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

Abstract

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).

Signaling and stress: The redox landscape in NOS2 biology

“…Furthermore, NO may play a critical role in increased angiogenesis and organization of the matrix for wound healing responses by suppressing tissue inhibitor of metallopeptidase 1 (TIMP1) while increasing the activity of matrix metalloproteinase (MMP)-9 [66], which degrades components of the extracellular matrix. NO mediated increases in MMP9 secretion and activity as well as reduced TIMP1 expression in microglial cells is critical for the elimination of plaques in murine models of Alzheimer's disease and in humans [67]. …”

“…In addition to nitrosation, protein nitration has been shown to modulate signaling pathways and disease outcome [67, 84, 163]. Increases in nitration of specific tyrosine residues can impact signaling, for example in mitochondria with dependence on fluctuations in O 2 tension [285].…”

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

“…In this regard, MMPs-2, -3, and -9 proteolytically degrade Ab. 219,230,231,232 Ridnour et al 233 showed that levels of Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] , a product of Ab metabolism by MMP-9, and MMP-9 activity were decreased in brain lysates of hAPPSwDI mice lacking nitric oxide synthase compared to their littermates expressing nitric oxide synthase. Based on these data, the authors concluded that nitric oxide is potentially involved in clearing plaques through increasing MMP-9 activity.…”

Matrix Metalloproteinase 9 in Epilepsy: The Role of Neuroinflammation in Seizure Development

“…Another substrate of MMP-9 responsible for changes in synapse structure and activity is synaptic cell adhesion molecule-2 (synCAM-2) [50]. Additionally, MMP-9 cleaves a postsynaptically localized protein, nectin-3 [51], and proteins responsible mainly for intrasynaptic transmission: β -amyloid peptide [52], insulin-like growth factor-binding proteins [53], and IL-1 β [54]. Also the change of the structure of dendritic spines may influence transmission within the synapse.…”