ApoE Influences the Blood-Brain Barrier Through the NF-κB/MMP-9 Pathway After Traumatic Brain Injury

Teng, Zhipeng; Guo, Zongduo; Zhong, Jian; Cheng, Chung–Ying; Huang, Zhijian; Wu, Yue; Tang, Shuang; Luo, Chao; Peng, Xing; Wu, Haitao; Sun, Xiaochuan; Jiang, Li

doi:10.1038/s41598-017-06932-3

Cited by 58 publications

(54 citation statements)

References 29 publications

(32 reference statements)

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“…These results suggest that endogenous apoE plays a vital role in the integrity of the BSCB after SCI. Our results are consistent with previous studies showing that apoE deficiency increases the permeability of blood-brain-barrier (BBB) in vivo and in vitro (Bell et al, 2012; Nishitsuji et al, 2011; Fullerton et al, 2001; Hafezi-Moghadam et al, 2007; Teng et al, 2017). For example, apoE −/− mice have been shown to increase BBB integrity damage in many animal models, such as brain injury (Methia et al, 2001; Teng et al, 2017), hyperlipidemia, and/or atherosclerosis, and aged mice (Grinberg and Thal, 2010; Badaut et al, 2012).…”

Section: Discussionsupporting

confidence: 93%

“…Our results are consistent with previous studies showing that apoE deficiency increases the permeability of blood-brain-barrier (BBB) in vivo and in vitro (Bell et al, 2012; Nishitsuji et al, 2011; Fullerton et al, 2001; Hafezi-Moghadam et al, 2007; Teng et al, 2017). For example, apoE −/− mice have been shown to increase BBB integrity damage in many animal models, such as brain injury (Methia et al, 2001; Teng et al, 2017), hyperlipidemia, and/or atherosclerosis, and aged mice (Grinberg and Thal, 2010; Badaut et al, 2012). Since BSCB plays an important role in maintaining the microenvironment and normal functions of the spinal cord, disruption of BSCB caused by SCI leads to the leakage of blood constituents, such as inflammation cells, immune proteins and other large molecules, which collectively initiate and/or contribute to a “vicious cycle” of pathophysiological processes, resulting in progressive tissue loss and neurological deficits after injury (Popovich et al, 1996; Whetstone et al, 2003).…”

Section: Discussionsupporting

confidence: 93%

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Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Cheng

Zheng

et al. 2018

Experimental Neurology

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Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE−/−) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3 days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE−/− mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE−/− mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE−/− mice. At 42 days after injury, the inflammation was still robust in the injured spinal cord in apoE−/− but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE−/− mice. The spared white matter was significantly decreased in apoE−/− mice compared to wild type ones. Locomotor function was significantly decreased in apoE−/− mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE−/− mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE−/− mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Cheng

Zheng

et al. 2018

Experimental Neurology

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“…Furthermore, individuals carrying the APOE4 gene in Alzheimer’s Disease display accelerated pericyte degeneration [ 22 ]. A recent experimental TBI paper also found that whole cortex homogenates from APOE4 mice have reduced tight protein compared to APOE3 mice at 7 days post-injury, alongside increased MMP-9 activity [ 76 ]. Our results show that at 10 days post-injury, closure of the BBB has occurred in APOE3 mice.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury

Main

Villapol

Sloley

et al. 2018

Mol Neurodegeneration

103

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BackgroundTraumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)–Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated.MethodsWe exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI.ResultsIn C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight-junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI.We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice.ConclusionsThese data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI.

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“…Overall, APOE tends to maintain BBB integrity and promote neurological recovery. While APOE-deficiency provokes BBB dysfunction, exogenously administered APOE or its mimetic peptides preserve BBB integrity in experimental studies [197][198][199][200][201][202][203].…”

Section: The Bbb Integrity-promoting Effects Of Astrocytesmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocytederived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporalenvironment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies.

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ApoE Influences the Blood-Brain Barrier Through the NF-κB/MMP-9 Pathway After Traumatic Brain Injury

Cited by 58 publications

References 29 publications

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

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