Augmented delayed infarct expansion and reactive astrocytosis after permanent focal ischemia in apolipoprotein E4 knock-in mice.
Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we aimed to examine whether an apoE isoform-specific exacerbation of delayed infarct expansion occurs after permanent middle cerebral artery occlusion (pMCAO). Compared with 2/2- or 3/3-KI mice, 4/4-KI mice exhibited significantly larger infarct volumes and worse neurologic deficits after pMCAO, with no significant differences between the latter two groups. Infarct volume in 4/4-KI mice was significantly increased from 1 to 5 days after pMCAO, whereas that in 2/2- or 3/3-KI mice was not significantly altered. DNA fragmentation in the peri-infarct area as detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatenick end-labeling was increased to a similar degree in all of the KI mice by 5 days after pMCAO, with no significant differences among the mouse groups. At every time-point examined, human apoE was most markedly expressed in the peri-infarct area, with similar immunoreactivity among the three lines of KI mice. The glial fibrillary acidic protein immunoreactive burden in the peri-infarct area was progressively increased through 7 days in 4/4-KI mice, but not in 2/2- or 3/3-KI mice. Taken together, these data show that the apoE4 isoform acts to aggravate delayed infarct expansion and peri-infarct reactive astrocytosis during the subacute phase of pMCAO in genetically engineered apoE-KI mice.
Mori
Takashi
T
Institute of Laboratory Animal Science, Saitama Medical Center/School, Kawagoe, Saitama, Japan. t_mori@saitama-med.ac.jp
Town
Terrence
T
Kobayashi
Mariko
M
Tan
Jun
J
Fujita
Shinobu C
SC
Asano
Takao
T
D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms