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 24h and 48h 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.
Research Unit of Pharmacology, Department of Clinical Pharmacy, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan.
Nobuhiro
N
Osada
Yasuhiro
Y
Kosuge
Tetsuroh
T
Kihara
Kumiko
K
Ishige
Yoshihisa
Y
Ito
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D015153:Blotting, Western; D053454:Caspase 12 / Q000378:metabolism; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D016548:Prosencephalon / Q000473:pathology*; D015427:Reperfusion Injury / Q000473:pathology
D001057:Apolipoproteins E; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D048031:JNK Mitogen-Activated Protein Kinases; D053454:Caspase 12