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

ABSTRACT: Cerebral amyloid angiopathy (CAA), the deposition of amyloid-? in cerebrovascular walls, is the most common cause of lobar hemorrhagic stroke. Previous studies show that cerebrovascular amyloid-? 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.

SUBMITTER: Zhao L

PROVIDER: S-EPMC4609585 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Zhao Lingzhi L Arbel-Ornath Michal M Wang Xueying X Betensky Rebecca A RA Greenberg Steven M SM Frosch Matthew P MP Bacskai Brian J BJ

Neurobiology of aging 20150716 11

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 severi ...[more]

PMID: 26248866

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Project description:BackgroundIntracerebral hemorrhage (ICH) recurrence risk is known to be higher in patients with cerebral amyloid angiopathy (CAA) as compared to other causes of ICH. Risk factors for ICH recurrence are not completely understood, and our goal was to study specific imaging microangiopathy markers.MethodsRetrospective case-control study of patients with non-traumatic ICH admitted to a single center between 2014 and 2017 who underwent magnetic resonance imaging (MRI). Clinical characteristics of the index event and occurrence of death and ICH recurrence were collected from clinical records. MRI images were independently reviewed by 2 neuroradiologists. Groups of patients with CAA-related and CAA-unrelated ICH defined were compared. Presence of CAA was defined according to the Boston modified criteria. Survival analysis with Kaplan-Meier curves and Cox-regression analyses was performed to analyze ICH recurrence-free survival.ResultsAmong 448 consecutive patients with non-traumatic ICH admitted during the study period, 104 were included in the study, mean age 64 years (±13.5), median follow-up of 27 months (interquartile range, IQR 16-43), corresponding to 272 person-years of total follow-up. CAA-related ICH patients presented higher burden of lobar microbleeds (p < 0.001), higher burden of enlarged perivascular spaces (EPVS) in centrum semiovale (p < 0.001) and more frequently presented cortical superficial siderosis (cSS; p < 0.001). ICH recurrence in patients with CAA was 12.7 per 100 person-years, and no recurrence was observed in patients without CAA. Variables associated with ICH recurrence in the whole population were age (hazard ratio [HR] per 1-year increment = 1.05, 95% CI 1.00-1.11, p = 0.046), presence of disseminated cSS (HR 3.32, 95% CI 1.09-10.15, p = 0.035) and burden of EPVS in the centrum semiovale (HR per 1-point increment = 1.80, 95% CI 1.04-3.12, p = 0.035).ConclusionsThis study confirms a higher ICH recurrence risk in patients with CAA-related ICH and suggests that age, disseminated cSS, and burden of EPVS in the centrum semiovale are associated with ICH recurrence.

Project description:Background and purposeCerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced.MethodsTg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined β-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes.ResultsMinocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls.ConclusionsMinocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.

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

Publications

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

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