Apolipoprotein E-deficient mice are more vulnerable to ER stress after transient forebrain ischemia

Apolipoprotein E-deficient (apoE−/−) mice have been shown to have increased vulnerability to neuronal damage induced by cerebral ischemia; however, the mechanism of this increased vulnerability remains unclear. In order to define the role of the apoE protein against ischemia-induced ER stress and cell death, experiments were performed to compare ER stress-associated chaperones and signal proteins in the hippocampus of apoE−/− mice to those of WT mice after being subjected to forebrain ischemia and reperfusion. Although neuronal loss in area CA1–CA3 of the hippocampus was observed 3 days after ischemia in both types of mice, the damage in apoE−/− mice was more severe. In apoE−/− mice, a more extensive increase in 78-kDa glucose-regulated protein (GRP78) was observed after the insult, whereas the level of GRP94 was not changed. The expression of both C/EBP homologous protein (CHOP) and caspase-12 was increased in the hippocampus in both WT and apoE−/− mice after ischemia. The increased levels of CHOP in apoE−/− mice were significantly higher than those in WT mice, whereas the levels of caspase-12 in the two were comparable. Furthermore, whereas the levels of c-Jun N-terminal kinase (JNK), p-JNK1 and p-JNK2 in WT mice were unchanged after ischemia, they were significantly increased in apoE−/− mice 24 h and 48 h after ischemia. These results suggest that increased vulnerability of the hippocampus to forebrain ischemia and reperfusion in apoE−/− mice is at least partly attributable to perturbed induction of an ER chaperone, GRP 94, and enhancement of the CHOP- and JNK-dependent apoptotic pathway in the hippocampus.