Apolipoprotein E deficiency exacerbates blood-brain barrier disruption and hyperglycemia-associated hemorrhagic transformation after ischemic stroke

Abstract

BackgroundThe polymorphism of the apolipoprotein E (ApoE) gene has been implicated in both the susceptibility to neurodegenerative disease and the prognosis of traumatic brain injury (TBI). However, the influence of ApoE on the risk of hemorrhagic transformation (HT) after acute ischemic stroke remains inconclusive. The present study aimed to investigate the potential impact of ApoE deficiency on the risk of hyperglycemia-associated HT and to elucidate the underlying mechanisms. MethodsWild-type (WT) and ApoE knockout (ApoE−/−) mice were injected with 50 % glucose to induce hyperglycemia and subsequently subjected to 90 min of intraluminal middle cerebral artery occlusion (MCAO). The mortality, neurological function, HT incidence and HT grading-score were evaluated at 24 hours after reperfusion. To evaluate the integrity of blood-brain barrier (BBB), the immunoglobulin G (IgG) leakage and the protein expressions of tight junctions (TJs) were detected using immunofluorescent staining and western blotting. Finally, the levels of matrix metalloproteinases (MMP)-2/9, microglial activation and proinflammatory mediators were investigated using immunofluorescent staining and western blotting. ResultsApoE−/− mice exhibited increased mortality and exacerbated neurological impairment, concomitant with more severe hyperglycemia-associated HT 24 hours post-reperfusion. Meanwhile, ApoE deficiency exacerbated the disruption of BBB, characterized by increased leakage of IgG, aggravated degradation of TJs and microvascular basement membranes. Furthermore, ApoE deficiency further aggravated the upregulation of MMP-2/9 and microglia-triggered neuroinflammation. ConclusionsOur findings demonstrate that the absence of ApoE exacerbates neurological impairment and hyperglycemia-associated HT in ischemic stroke mice, which is closely associated with MMP-2/9 signaling and neuroinflammation-mediated disruption of BBB.