Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice
Open Access
- 21 May 2009
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 109 (6), 1636-1647
- https://doi.org/10.1111/j.1471-4159.2009.06096.x
Abstract
Cerebral amyloid angiopathy (CAA), characterized by extracellular β-amyloid peptide (Aβ) deposits in vessel walls, is present in the majority of cases of Alzheimer’s disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Aβ are poorly understood, extracellular matrix metalloproteinases (MMP) and Aβ-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microcopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with α-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (∼50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (∼30–40% reduction) but also oxidative stress (∼40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with α-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Aβ-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.Keywords
This publication has 55 references indexed in Scilit:
- Cerebral Cortical Arteriolar Angiopathy, Vascular Beta-Amyloid, Smooth Muscle Actin, Braak Stage, and APOE GenotypeStroke, 2008
- Oxidative Stress and Matrix Metalloproteinase-9 in Acute Ischemic StrokeStroke, 2008
- A limited role for microglia in antibody mediated plaque clearance in APP miceNeurobiology of Disease, 2007
- Metalloproteinases and Vulnerable Atherosclerotic PlaquesTrends in Cardiovascular Medicine, 2007
- Antibody-Mediated Clearance of Amyloid-β Peptide from Cerebral Amyloid Angiopathy Revealed by QuantitativeIn VivoImagingJournal of Neuroscience, 2007
- Reduction of Tissue Plasminogen Activator-Induced Matrix Metalloproteinase-9 by Simvastatin in AstrocytesStroke, 2006
- Kinetics of Cerebral Amyloid Angiopathy Progression in a Transgenic Mouse Model of Alzheimer DiseaseJournal of Neuroscience, 2006
- Tuftsin Fragment 1–3 Is Beneficial When Delivered After the Induction of Intracerebral HemorrhageStroke, 2005
- Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in VivoJournal of Biological Chemistry, 2005
- Pathogenic Aβ induces the expression and activation of matrix metalloproteinase‐2 in human cerebrovascular smooth muscle cellsJournal of Neurochemistry, 2003