Neuronal injury is the primary cause of poor outcome after
subarachnoid hemorrhage (SAH). The
apolipoprotein E (
APOE) gene has been suggested to be involved in the prognosis of SAH patients. However, the role of
APOE in neuronal injury after SAH has not been well studied. In this study, SAH was induced in
APOE-knockout (
APOE-/-) and wild-type (WT) mice to investigate the impact of
APOE deficiency on neuronal injury in the early phase of SAH. The experiments of this study were performed in murine SAH models in vivo and primary cultured microglia and neurons in vitro. The SAH model was induced by endovascular perforation in
APOE-/- and
APOE WT mice. The mortality rate,
weight loss, and neurological deficits were recorded within 72 h after SAH. The neuronal injury was assessed by detecting the neuronal apoptosis and axonal injury. The activation of microglia was assessed by immunofluorescent staining of Iba-1, and
clodronate liposomes were used for inhibiting microglial activation. The expression of JNK/c-Jun was evaluated by immunofluorescent staining or western blotting. The expression of TNF-α, IL-1β, and
IL-6 was evaluated by ELISA. Primary cultured microglia were treated with
hemoglobin (Hb) in vitro for simulating the pathological process of SAH.
SP600125, a JNK inhibitor, was used for evaluating the role of JNK in
neuroinflammation.
Nitrite production was detected for microglial activation, and flow cytometry was performed to detect apoptosis in vitro. The results suggested that SAH induced early neuronal injury and neurological deficits in mice.
APOE deficiency resulted in more severe neurological deficits after SAH in mice. The neurological deficits were associated with exacerbation of neuronal injury, including neuronal apoptosis and axonal injury. Moreover,
APOE deficiency enhanced microglial activation and related inflammatory injury on neurons. Inhibition of microglia attenuated neuronal injury in mice, whereas inhibition of JNK inhibited microglia-mediated inflammatory response in vitro. Taken together, JNK/c-Jun was involved in the enhancement of microglia-mediated inflammatory injury in
APOE-/- mice.
APOE deficiency aggravates neuronal injury which may account for the poor neurological outcomes of
APOE-/- mice. The possible protective role of
APOE against EBI via the modulation of inflammatory response indicates its potential treatment for SAH.