title: Increased vulnerability to focal ischemic brain injury in human apolipoprotein E4 knock-in mice.
abstract: Accumulating evidence suggests that among the 3 human apolipoprotein E (apoE) isoforms encoded by the human APOE gene, the e4 allele may act to exacerbate brain damage in humans and animals. This study aimed to compare the isoform-specific vulnerability conferred by human apoE to ischemic brain damage, using mice expressing human apoE isoforms (apoE2, apoE3, or apoE4) in place of mouse apoE, produced by the gene-targeting technique in embryonic stem cells (knock-in, KI). Homozygous human apoE2 (2/2), apoE3 (3/3), or apoE4 (4/4) KI mice were subjected to permanent focal cerebral ischemia by a modified intraluminal suture method. Twenty-four h thereafter, brain damage, (as estimated by infarct volume and neurologic deficit) was significantly worse in 4/4 KI mice versus 2/2 or 3/3 KI mice (p < 0.001 for each comparison), with no significant differences between 2/2 and 3/3 KI mice. Immunohistochemistry for human apoE expression revealed similar apoE distribution with no significant difference in the immunostaining intensity among the 3 lines of KI mice. Notably. increased expression of human apoE was detected in neurons and astrocytes in the peri-infarct area, and a punctate expression pattern was evident in the border between the infarct and peri-infarct areas in all KI mice subjected to ischemia. Taken together, our results show that apoE affects the outcome of acute brain damage in an isoform-specific fashion (apoE4 > apoE3 = apoE2) in genetically engineered mice.
authors.affiliation: Institute of Laboratory Animal Science, Department of Neurosurgery, Saitama Medical Center/School, Kawagoe, Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Shinobu C
authors.initials: SC
authors.lastname: Fujita
authors.forename: Takao
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms