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

Monica Garcia-Alloza, Claudia Prada, Carli Lattarulo, Sara Fine, Laura A. Borrelli, Rebecca Betensky, Steven M. Greenberg, Matthew P. Frosch, Brian J. Bacskai

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1636-1647
Number of pages12
JournalJournal of Neurochemistry
Volume109
Issue number6
DOIs
StatePublished - Jun 2009

Keywords

  • Antioxidant
  • MMP inhibitor
  • Matrix metalloproteinases
  • Multiphoton microscopy
  • Oxidative stress
  • Transgenic mouse

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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