title: Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy.
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.
authors.affiliation: Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Arbel-Ornath
authors.affiliation: Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.affiliation: Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.affiliation: Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA; C.S. Kubik Laboratory of Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: bbacskai@partners.org.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index
chemical_list: D016229:Amyloid beta-Peptides; D011994:Recombinant Proteins; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Amyloid-β; Cerebral amyloid angiopathy (CAA); Intracerebral hemorrhage; Matrix metalloproteinase (MMP); Multiphoton microscopy