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

Abstract

Cerebral amyloid angiopathy (CAA), the deposition of β-amyloid (Aβ) in cerebrovascular walls, is the most common cause of lobar hemorrhagic stroke. Previous studies show that cerebrovascular Aβ induces expression and activation of matrix metalloproteinase 9 (MMP-9) in cerebral vessels of amyloid precursor protein (APP) transgenic mice. Here we extended these findings and evaluated MMP-9 expression in postmortem brain tissues of human CAA cases. MMP-9 co-localized with CAA, correlated with the severity of the vascular pathology, and was detected in proximity to microbleeds. We characterized a novel assay using longitudinal multi-photon microscopy and a novel tracer to visualize and quantify the magnitude and kinetics of hemorrhages in 3-dimensions in living mouse brains. We demonstrated that topical application of recombinant MMP-9 resulted in a time- and dose-dependent cerebral hemorrhage. APP 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.

Blood-Brain Barrier Dysfunction in Small Vessel Disease Related Intracerebral Hemorrhage

“…Of the sixteen included studies, one assessed BBB dysfunction in HV-related ICH ( n = 82) ( 36 ) six in CAA-related ICH ( n = 117) ( 37 – 42 ), and nine did not specify the underlying etiology of the ICH ( n = 489; Tables 2A , 2B , S4 ) ( 44 – 52 ).…”

“…Of six studies that assessed CAA-related BBB dysfunction, five studies found evidence for ICH-associated BBB dysfunction. Three studies assessed BBB abnormalities as defined by altered gelatinase levels in cortical vessels ( 38 , 42 ), cerebral tissue ( 38 ), plasma ( 38 ), and CSF ( 41 ), in patients with CAA. The first study identified an increased percentage of MMP-2 positive cortical vessels in moderately to severely Aβ affected vessels from CAA patients compared with not to mildly affected cortical vessels of the same patients ( n = 6) and cortical vessels of non-CAA controls ( n = 3).…”

Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage

“…Microglial activation results in the production of matrix metalloproteinases (MMPs), a family of potent proteinases involved in remodeling of extracellular matrix and regulation of the BBB. 69 Secretion of MMPs has been observed in the perihematomal region in experimental models of ICH, [70][71][72][73][74] as well as in patients after hemorrhage. 72,75 These studies have found that MMP9 is particularly important for disruption of endothelial tight junctions, BBB remodeling, and increased vascular permeability after ICH, and high serum levels of MMP9 in ICH patients are associated with hematoma growth and poor clinical outcome.…”

Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications

“…27,[30][31][32] Deregulation of matrix metalloproteinases (MMP), specifically the MMP-9 species, has been suggested as an important contributor to CAA-associated hemorrhage. 33 These structural alterations likely affect vessel physiological function as well. 34 Ex vivo studies with isolated cerebral arterioles have shown that synthetic Aβ40 (and to a lesser degree Aβ42) induced direct vessel constriction, enhanced response to vasoconstrictors, and reduced response to vasodilators.…”