Behavioral phenotyping of GFAP-ApoE3 and-ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology

被引:131
作者
Hartman, RE
Wozniak, DF
Nardi, A
Olney, JW
Sartorius, L
Holtzman, DM
机构
[1] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Ctr Study Nervous Syst Injury, St Louis, MO 63110 USA
[5] Washington Univ, Dept Psychol, St Louis, MO 63130 USA
基金
美国国家卫生研究院;
关键词
Alzheimer's disease; apolipoprotein E; knockout mice; spatial learning and memory; reference memory; emotionality; sensorimotor;
D O I
10.1006/exnr.2001.7715
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
For the purpose of studying the potential neurobehavioral effects of different human apolipoprotein E (apoE) isoforms produced within the brain, transgenic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control of an astrocyte-specific, glial fibrillary acidic protein promoter and these TG mice were bred back to apoE knockout (KO) mice. Behavioral phenotypes of apoE3 and apoE4 TG mice were derived by conducting a longitudinal study in which apoE3 and apoE4 TG mice were compared with apoE KO and wild-type (WT) mice (all male) on several behavioral measures. Analysis of locomotor activity, "open-field" behaviors, acoustic startle/prepulse inhibition, and elevated plus maze data suggested that the apoE TG/KO groups were more "emotionally reactive" than WT mice, with apoE4 mice typically being the most reactive. The absence of performance differences among groups on the rotating holeboard and water navigation tasks suggested intact reference memory processing in apoE TG/KO mice. However, apoE4 mice were profoundly impaired on a working memory-based protocol in the radial arm maze (11-14 months). Nonassociative factors (sensorimotor capacities or emotionality differences) did not appear to confound interpretation of the learning/memory results. Western blot analysis revealed no alterations in the level of synaptic, neuronal, or glial markers in neocortex or hippocampus and histologic analysis revealed no evidence of A beta deposition or neuritic plaques in the apoE KO/TG mice. Our findings suggest that apoE4 expression in the brain may have selective deleterious effects on memory function in the absence of typical Alzheimer's-like neuropathology. (C) 2001 Academic Press.
引用
收藏
页码:326 / 344
页数:19
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