title: Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice.
abstract: 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.
authors.affiliation: Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
authors.forename: Claudia
authors.initials: C
authors.lastname: Prada
authors.forename: Carli
authors.initials: C
authors.lastname: Lattarulo
authors.forename: Sara
authors.initials: S
authors.lastname: Fine
authors.forename: Laura A
authors.initials: LA
authors.lastname: Borrelli
authors.forename: Rebecca
authors.initials: R
authors.lastname: Betensky
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
mesh_terms: D000475:Alkenes / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D053764:Presenilin-1 / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D013223:Statistics as Topic; D013267:Stilbenes; D013997:Time Factors
chemical_list: C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; D000475:Alkenes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001555:Benzene Derivatives; D003497:Cyclic N-Oxides; D004151:Dipeptides; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D013267:Stilbenes; C029217:phenyl-N-tert-butylnitrone; D019821:Simvastatin; D020782:Matrix Metalloproteinases; D008911:Minocycline