Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subarachnoid Hemorrhage in Mice

Abstract

Subarachnoid hemorrhage (SAH) is a neurologically destructive stroke in which early brain injury (EBI) plays a pivotal role in poor patient outcomes. Expanding upon our previous work, multiple techniques and methods were used in this preclinical study to further elucidate the mechanisms underlying the beneficial effects of apolipoprotein E (ApoE) against EBI after SAH in murine apolipoprotein E gene-knockout mice (Apoe, KO) and wild-type mice (WT) on a C57BL/6J background. We reported that Apoe deficiency resulted in a more extensive EBI at 48 h after SAH in mice demonstrated by MRI scanning and immunohistochemical staining and exhibited more extensive white matter injury and neuronal apoptosis than WT mice. These changes were associated with an increase in NADPH oxidase 2 (NOX2) expression, an important regulator of both oxidative stress and inflammatory cytokines. Furthermore, immunohistochemical analysis revealed that NOX2 was abundantly expressed in activated M1 microglia. The JAK2/STAT3 signaling pathway, an upstream regulator of NOX2, was increased in WT mice and activated to an even greater extent in Apoe mice; whereas, the JAK2-specific inhibitor, AG490, reduced NOX2 expression, oxidative stress, and inflammation in Apoe-deficient mice. Also, apoE-mimetic peptide COG1410 suppressed the JAK2/STAT3 signaling pathway and significantly reduced M1 microglia activation with subsequent attenuation of oxidative stress and inflammation after SAH. Taken together, apoE and apoE-mimetic peptide have whole-brain protective effects that may reduce EBI after SAH via M1 microglial quiescence through the attenuation of the JAK2/STAT3/NOX2 signaling pathway axis.

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

“…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].…”

Activation of Melanocortin 1 Receptor Attenuates Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage viathe Suppression of Neuroinflammation through AMPK/TBK1/NF-κB Pathway in Rats

“…Frequently, microglia are redeemed to exist in a resting status (M0). However, upon activation, they are transformed into two different phenotypes (M1 and M2) with distinct physiological functions [6,7]. M1 phenotype microglia are pro-inflammatory as they secrete inflammatory molecules, including IL-1β, IL-6, and TNF-α, which are greatly detrimental to the brain tissues [8].…”

Inflammation: a Good Research Target to Improve Outcomes of Poor-Grade Subarachnoid Hemorrhage

“…In endovascular perforation SAH models using adhesion molecule knockout mice, it was demonstrated that SAH resulted in early intravascular inflammation with the recruitment of circulating neutrophils to the vessel/brain interface and that the inhibition of neutrophilendothelial interaction prevented systemic inflammation from accumulating and activating microglia to cause neuronal cell death [19]. Extravasated blood components such as thrombin, platelets, and leukocytes also activate microglia, which is an important mechanism to produce proinflammatory cytokines, matricellular proteins, and oxidative stress, causing EBI in a mouse endovascular perforation model [20,21]. At 24 h after experimental SAH by endovascular perforation in rats, magnetic resonance imaging studies showed that more severe SAH caused a more frequent and larger cerebral infarction, where fibrinogen/fibrin-stained microthromboses were histologically found [22].…”