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

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.