19457117

pubmed:Citation

6

Cerebral amyloid angiopathy (CAA), characterized by extracellular beta-amyloid peptide (Abeta) 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 Abeta are poorly understood, extracellular matrix metalloproteinases (MMP) and Abeta-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 microscopy 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 alpha-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (approximately 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 (approximately 30-40% reduction) but also oxidative stress (approximately 40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with alpha-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Abeta-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.

eng

IM

MEDLINE

1471-4159

Electronic

NLM

1636-47

pubmed-meshheading:19457117-Alkenes, pubmed-meshheading:19457117-Amyloid beta-Peptides, pubmed-meshheading:19457117-Amyloid beta-Protein Precursor, pubmed-meshheading:19457117-Animals, pubmed-meshheading:19457117-Benzene Derivatives, pubmed-meshheading:19457117-Cerebral Amyloid Angiopathy, pubmed-meshheading:19457117-Cyclic N-Oxides, pubmed-meshheading:19457117-Dipeptides, pubmed-meshheading:19457117-Fluorescent Dyes, pubmed-meshheading:19457117-Humans, pubmed-meshheading:19457117-Hydroxymethylglutaryl-CoA Reductase Inhibitors, pubmed-meshheading:19457117-Matrix Metalloproteinases, pubmed-meshheading:19457117-Mice, pubmed-meshheading:19457117-Mice, Transgenic, pubmed-meshheading:19457117-Minocycline, pubmed-meshheading:19457117-Oxidative Stress, pubmed-meshheading:19457117-Presenilin-1, pubmed-meshheading:19457117-Protease Inhibitors, pubmed-meshheading:19457117-Reactive Oxygen Species, pubmed-meshheading:19457117-Simvastatin, pubmed-meshheading:19457117-Statistics as Topic, pubmed-meshheading:19457117-Time Factors

Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural