Apolipoprotein E polymorphism impacts white matter injury through microglial phagocytosis after experimental subarachnoid hemorrhage

by Selleckchem | Sep 14 2023

Apolipoprotein E (apoE, protein; APOE, gene), divided into three alleles of E2, E3 and E4 in humans, is associated with the progression of white matter lesion load. However, mechanism evidence has not been reported regarding the APOE genotype in early white matter injury (WMI) under subarachnoid hemorrhage (SAH) conditions. In the present study, we investigated the effects of APOE gene polymorphisms, by constructing microglial APOE4 and APOE4-specific overexpression, on WMI and underlying mechanisms of microglia phagocytosis in a mice model of SAH. A total of 167 male C57BL/6J mice (weight 22-26 g) were used. SAH and bleeding environment were induced by endovascular perforation in vivo and oxyHb in vitro, respectively. Multi-technology approaches, including immunohistochemistry, high throughput sequencing, gene editing for adeno-associated viruses, and several molecular biotechnologies were used to validate the effects of APOE polymorphisms on microglial phagocytosis and WMI after SAH. Our results revealed that APOE4 significantly aggravated the WMI and decreased neurobehavioral function by impairing microglial phagocytosis after SAH. Indicators negatively associated with microglial phagocytosis increased like CD16, CD86 and the ratio of CD16/CD206, while the indicators positively associated with microglial phagocytosis decreased like Arg-1 and CD206. The increased ROS and aggravating mitochondrial damage demonstrated that the damaging effects of APOE4 in SAH may be associated with microglial oxidative stress-dependent mitochondrial damage. Inhibiting mitochondrial oxidative stress by Mitoquinone (mitoQ) can enhance the phagocytic function of microglia. In conclusion, anti-oxidative stress and phagocytosis protection may serve as promising treatments in the management of SAH.

Comments:

In this study, the researchers aimed to investigate the effects of different variants of the apolipoprotein E (APOE) gene, specifically APOE4, on white matter injury (WMI) and microglial phagocytosis in a mouse model of subarachnoid hemorrhage (SAH). APOE is a protein associated with lipid metabolism and has three common alleles in humans: E2, E3, and E4.

The researchers conducted experiments using male C57BL/6J mice and induced SAH and bleeding by endovascular perforation in vivo and oxyhemoglobin (oxyHb) exposure in vitro. They employed various techniques such as immunohistochemistry, high-throughput sequencing, gene editing using adeno-associated viruses, and molecular biotechnologies to evaluate the effects of APOE gene polymorphisms on microglial phagocytosis and WMI after SAH.

The results of the study indicated that APOE4 significantly worsened WMI and decreased neurobehavioral function by impairing microglial phagocytosis following SAH. Several indicators associated with microglial phagocytosis were affected by APOE4. The levels of CD16, CD86, and the ratio of CD16/CD206, which are negatively associated with microglial phagocytosis, increased. Conversely, the levels of Arg-1 and CD206, which are positively associated with microglial phagocytosis, decreased. The researchers also observed increased reactive oxygen species (ROS) and exacerbated mitochondrial damage, suggesting that the damaging effects of APOE4 in SAH may be linked to microglial oxidative stress-dependent mitochondrial damage.

Furthermore, the researchers found that inhibiting mitochondrial oxidative stress using Mitoquinone (mitoQ) enhanced the phagocytic function of microglia. These findings suggest that targeting oxidative stress and promoting phagocytosis could be potential therapeutic strategies for managing SAH.

In summary, this study demonstrated that APOE4 variant exacerbates white matter injury and impairs microglial phagocytosis in a mouse model of SAH. The results suggest that protecting against oxidative stress and enhancing phagocytic function could be promising approaches for the treatment of SAH.