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Behavioral phenotyping of GFAP-ApoE3 and -ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer’s-like neuropathology.
Abstract
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 Abeta deposition or neuritic plaques…
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“Hartman et al. also demonstrated that apoE4 mice were more severely impaired in working memory in a radial arm maze test (Hartman et al., 2001).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Hartman et al., 2001
In the citing paper
“and were more severely impaired in learning and memory (Hartman et al., 2001; Raber et al., 1998; Raber et al., 2000).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Hartman et al., 2001
In the citing paper
“Some studies show no significant cognitive impairments compared to either wild type or human apoE3 expressing mice (Raber et al., 1998, Grootendorst et al., 2005, Hartman et al., 2001, van Meer et al., 2007)”
From Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner (2014) · cites this paper as Hartman et al., 2001
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ApoE isoform‐dependent deficits in extinction of contextual fear conditioning
Olsen, R. H. J., Agam, M., Davis, M. J., & Raber, J. (2012) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00833.x · Cited by 35
APOE 4 polymorphism results in early cognitive deficits in an EAE model
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Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice
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Apolipoprotein E Regulates Injury-Induced Activation of Hippocampal Neural Stem and Progenitor Cells
Hong, S. J., Washington, P. M., Kim, A., Yang, C.-P., Yu, T., & Kernie, S. G. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2014.3860 · Cited by 33
Mortality is associated with apolipoprotein E ɛ4 in nondemented adults with Down syndrome
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Reduced neuronal signaling in the ageing apolipoprotein-E4 targeted replacement female mice
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Behavioral Consequences of NMDA Antagonist-Induced Neuroapoptosis in the Infant Mouse Brain
Yuede, C. M., Wozniak, D. F., Creeley, C. E., Taylor, G. T., Olney, J. W., & Farber, N. B. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011374 · Cited by 29
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Opposing Roles of apolipoprotein E in aging and neurodegeneration
Hudry, E., Klickstein, J., Cannavo, C., Jackson, R., Muzikansky, A., Gandhi, S., Urick, D., Sargent, T., Wrobleski, L., Roe, A. D., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900325 · Cited by 30
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Apolipoprotein E Is a Prime Suspect, Not Just an Accomplice, in Alzheimer's Disease
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Metadata
- Authors
- Hartman, R. E., Wozniak, D. F., Nardi, A., Olney, J. W., Sartorius, L., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Wozniak, D.F.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2001-08
- Volume
- 170
- Issue
- 2
- Pages
- 326-344
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2017595192
- Cited by
- 157
- References
- 36
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 8 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 7 · 2013: 12 · 2012: 14
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG11355-06, AG13956, P01AG011355)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E, APOE ε4, APOE3, transgenic mice, GFAP promoter, astrocytes, working memory, reference memory, emotional reactivity, acoustic startle response, prepulse inhibition, radial maze, hippocampus, neocortex, Alzheimer's disease
- MeSH terms
- Acoustic Stimulation, Aging, Alzheimer Disease, Analysis of Variance, Animals, Apolipoproteins E, Cues, Emotions, Escape Reaction, Glial Fibrillary Acidic Protein, Humans, Learning, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Phenotype, Promoter Regions, Genetic, Reaction Time, Space Perception, Reflex, Startle, Time Factors, Mice, Knockout, Mice, Apolipoprotein E3, Apolipoprotein E4
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