An apolipoprotein E receptor mimetic peptide decreases blood-brain barrier permeability following intracerebral hemorrhage by inhibiting the CypA/MMP-9 signaling pathway via LRP1 activation

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作者: Jun, Tan ; Wang, Long ; Hang, Hang ; Wang, Ningning ; Wu, Guofeng ; Wang, Likun ; Chen, Xing ; Ren, Siyin ; Li, Chen

Apolipoprotein (Apo) E mimetic peptides down-regulate the inflammatory response and alleviate damage to secondary neurons after intracerebral hemorrhage (ICH). We designed a novel apoE receptor mimetic composed of the low-density lipoprotein receptor-associated protein-1 (LRP1) receptor-binding domain of apoE with 6 lysines (6KApoEp). The 6KApoEp peptide is small enough to penetrate the blood-brain barrier (BBB) and modulate the inflammatory response during damage to the central nervous system. LRP1 inhibits the CypA/MMP-9 pathway and reduces BBB damage. Thus, we examined the effects of 6KApoEp-LRP1 interaction. LRP1 and 6KApoEp interacted and co-localized in the pericytes. We established a Sprague-Dawley (SD) male rat model of ICH to observe the role of 6KApoEp in secondary injury after ICH. The expression levels of cyclophilin A (CypA), nuclear factor kappa-B (NF-κB) p65, and matrix metalloproteinase 9 (MMP-9) were increased, the expression levels of ZO-1, claudin-5, and occludin were decreased, and brain water content and BBB permeability increased in the ICH model. The expression of CypA, NF-κB, and MMP-9 decreased significantly around the hematoma, while the expression of tight junction-related proteins increased significantly in response to 6KApoEp, especially at the 100 μg/kg dose. LRP expression increased around the ICH focus in response to 6KApoEp treatment, thus increasing the influence on the expression of CypA, NF-κB, and MMP-9. We conclude that 6KApoEp inhibits the CypA/NF-κB/MMP-9 pathway by activating LRP1, resulting in reduced BBB damage and less brain edema around the ICH. These results provide the theoretical basis for improving the prognosis and treatment of ICH. Our results suggest that 6KApoEp activates LRP1, resulting in the attenuation of tight junction protein degradation (ZO-1, occludin, and claudin-5) via the CypA/NF-κB/MMP-9 signaling pathway. The increased tight junction protein levels improve the BBB and attenuate edema development in brain tissue around the hematoma following ICH.

2017-06-01·Translational stroke research2区 · 医学

Inhibition of Blood-Brain Barrier Disruption by an Apolipoprotein E-Mimetic Peptide Ameliorates Early Brain Injury in Experimental Subarachnoid Hemorrhage

2区 · 医学

Article

作者: Chen, Ligang ; Yang, Ping ; Vitek, Michael P ; Sun, Xiaochuan ; Kuai, Li ; Jiang, Yong ; Chen, Yue ; Pang, Jinwei ; Chen, Yitian ; Wu, Yue ; Peng, Jianhua

Apolipoprotein E (ApoE)-mimetic peptides have been demonstrated to be beneficial in secondary brain injury following experimental subarachnoid hemorrhage (SAH). However, the molecular mechanisms underlying these benefits in SAH models have not been clearly identified. This study investigated whether an ApoE-mimetic peptide affords neuroprotection in early brain injury (EBI) following SAH by attenuating BBB disruption. SAH was induced by an endovascular perforation in young, healthy, male wild-type (WT) C57BL/6J mice. Multiple techniques, including MRI with T2-weighted imaging, ¹⁸ FDG PET-CT scanning and histological studies, were used to examine BBB integrity and neurological dysfunction in EBI following SAH. We found that SAH induced a significant increase of BBB permeability and neuron apoptosis, whereas ApoE-mimetic peptide treatment significantly reduced the degradation of tight junction proteins and endothelial cell apoptosis. These effects reduced brain edema and neuron apoptosis, increased cerebral glucose uptake, and improved neurological functions. Further investigation revealed that the ApoE-mimetic peptide inhibited the proinflammatory activators of MMP-9, including CypA, NF-κB, IL-6, TNF-α, and IL-1β, thereby ameliorating BBB disruption at the acute stage of SAH. Together, these data indicate that ApoE-mimetic peptide may be a novel and promising therapeutic strategy for EBI amelioration after SAH that are worthy of further study.

2009-06-01·Neurobiology of disease2区 · 医学

Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer's disease

2区 · 医学

Article

作者: G.M. Anantharamaiah ; Shaila P. Handattu ; Mayakonda N. Palgunachari ; Ling Li ; Gaurav Nayyar ; Thomas van Groen ; Candyce E. Monroe ; Inga Kadish ; Dongfeng Cao ; David W. Garber

Recent evidence indicates that inflammation may significantly contribute to the pathogenesis of Alzheimer's disease (AD). Since the apo A-I mimetic peptide D-4F has been shown to inhibit atherosclerotic lesion formation and regress already existing lesions (in the presence of pravastatin) and the peptide also decreases brain arteriole inflammation, we undertook a study to evaluate the efficacy of oral D-4F co-administered with pravastatin on cognitive function and amyloid beta (A beta) burden in the hippocampus of APPSwe-PS1 Delta E9 mice. Three groups of male mice were administered D-4F and pravastatin, Scrambled D-4F (ScD-4F, a control peptide) and pravastatin in drinking water, while drinking water alone served as control. The escape latency in the Morris Water Maze test was significantly shorter for the D-4F+statin administered animals compared to the other two groups. While the hippocampal region of the brain was covered with 4.2+/-0.5 and 3.8+/-0.6% of A beta load in the control and ScD-4F+statin administered groups, in the D-4F+statin administered group A beta load was only 1.6+/-0.1%. Furthermore, there was a significant decrease in the number of activated microglia (p<0.05 vs the other two groups) and activated astrocytes (p<0.05 vs control) upon oral D-4F+statin treatment. Inflammatory markers TNFalpha and IL-1 beta levels were decreased significantly in the D-4F+statin group compared to the other two groups (for IL-1 beta p<0.01 vs the other two groups and for TNF-alpha p<0.001 vs control) and the expression of MCP-1 were also less in D-4F+statin administered group compared to the other two groups. These results suggest that the apo A-I mimetic peptide inhibits amyloid beta deposition and improves cognitive function via exerting anti-inflammatory properties in the brain.

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