title: Overexpression of apolipoprotein E4 increases kainic-acid-induced hippocampal neurodegeneration.
abstract: Apolipoprotein E (apoE) has an intricate biological function in modulating immune responses and apoE isoforms exhibit diverse effects on neurodegenerative and neuroinflammatory disorders. In the present study, we investigated the individual roles of apoE isoforms in the kainic acid (KA)-induced hippocampal neurodegeneration with focus on immune response and microglia functions. ApoE2, 3 and 4 transgenic mice as well as wild-type (WT) mice were treated with KA by intranasal route. ApoE4 overexpressing mice revealed several peculiarities as compared with other transgenic mice and WT mice, i.e. (1) they had more severe KA-induced seizures than apoE2 and 3 mice, (2) they exhibited neuron loss in hippocampus that was higher than in apoE2, 3 and WT mice, (3) KA administration resulted in higher counts of their head drops in the cross-area of elevated plus-maze, (4) they showed lower KA-induced rearing activity than apoE2 mice in the open-field test, (5) their KA-induced microglial expression of MHC-II and CD86 was elevated compared to apoE3 mice, (6) the KA-induced increase of microglial iNOS was higher than that in the other groups of mice, and (7) the TNF-α and IL-6 expression was decreased 7 days after KA application compared to untreated mice and mice treated 1 day with KA. However, the signaling pathway of NFκB or Akt seemed not to be involved in apoE-isoform dependent susceptibility to KA-induced neurotoxicity. In conclusion, over-expression of apoE4 deteriorated KA-induced hippocampal neurodegeneration in C57BL/6 mice, which might result from a higher up-regulation of microglia activation compared to apoE2 and 3 transgenic mice and WT mice.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Xi-Jing
authors.initials: XJ
authors.lastname: Mao
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Zhang
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Zheng
authors.forename: Therese
authors.initials: T
authors.lastname: Pham
authors.forename: Abdu
authors.initials: A
authors.lastname: Adem
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Eilhard
authors.initials: E
authors.lastname: Mix
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D016207:Cytokines; D004797:Enzyme-Linked Immunosorbent Assay; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005106:Exploratory Behavior / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D012640:Seizures / Q000139:chemically induced; D018709:Statistics, Nonparametric
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D039481:CD11b Antigen; D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D007608:Kainic Acid