Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy

Lingzhi Zhao, Michal Arbel-Ornath, Xueying Wang, Rebecca A. Betensky, Steven M. Greenberg, Matthew P. Frosch, Brian J. Bacskai

Research output: Contribution to journalArticle

Abstract

Cerebral amyloid angiopathy (CAA), the deposition of amyloid-β in cerebrovascular walls, is the most common cause of lobar hemorrhagic stroke. Previous studies show that cerebrovascular amyloid-β induces expression and activation of matrix metalloproteinase 9 (MMP-9) in cerebral vessels of amyloid precursor protein transgenic mice. Here, we extended these findings and evaluated MMP-9 expression in postmortem brain tissues of human CAA cases. MMP-9 colocalized with CAA, correlated with the severity of the vascular pathology, and was detected in proximity to microbleeds. We characterized a novel assay using longitudinal multiphoton microscopy and a novel tracer to visualize and quantify the magnitude and kinetics of hemorrhages in three dimensions in living mouse brains. We demonstrated that topical application of recombinant MMP-9 resulted in a time- and dose-dependent cerebral hemorrhage. Amyloid precursor protein mice with significant CAA developed more extensive hemorrhages which also appeared sooner after exposure to MMP-9. Our data suggest an important role for MMP-9 in development of hemorrhages in the setting of CAA. Inhibition of MMP-9 may present a preventive strategy for CAA-associated hemorrhage.

Original languageEnglish (US)
Pages (from-to)2963-2971
Number of pages9
JournalNeurobiology of Aging
Volume36
Issue number11
DOIs
StatePublished - Nov 2015

Keywords

  • Amyloid-β
  • Cerebral amyloid angiopathy (CAA)
  • Intracerebral hemorrhage
  • Matrix metalloproteinase (MMP)
  • Multiphoton microscopy

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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