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Cited by 24Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Independent APOE4 knock‐in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines

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Sepulveda, Jordy, Luo, Nancy, Nelson, Matthew, Ng, Christi Anne S., Rebeck, George William·2022·Journal of Neurochemistry
DOI 10.1111/jnc.15665PMC PMC9613529
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Abstract

APOE is an immunomodulator in the brain and the major genetic risk factor for late‐onset Alzheimer's disease (AD). Targeted replacement APOE mice ( APOE ‐TR) have been a useful tool to study the effects of APOE isoforms on brain neurochemistry and activity prior to and during AD. We use newly available APOE knock‐in mice (JAX‐APOE) to compare phenotypes associated with APOE4 across models. Similar to APOE4‐TR mice, JAX‐E4 mouse brains showed 27% lower levels of APOE protein compared with JAX‐E3 ( p < 0.001). We analyzed several neuroinflammatory molecules that have been associated with APOE genotype. SerpinA3 was much higher in APOE4 ‐TR mice to APOE3 ‐TR mice, but this effect was not seen in JAX‐APOE mice. There were higher levels of IL‐3 in JAX‐E4 brains compared with JAX‐E3, but other neuroinflammatory markers (IL6, TNFα) were not affected by APOE genotype. In terms of neuronal structure, basal dendritic spine density in the entorhinal cortex was 39% lower in JAX‐E4 mice compared with JAX‐E3 mice ( p < 0.001), again similar to APOE‐TR mice. One‐week treatment with ibuprofen significantly increased dendritic spine density in the JAX‐E4 mice, consistent with our previous finding in APOE ‐TR mice. Behaviorally, there was no effect of APOE genotype on Barnes Maze learning and memory in 6‐month‐old JAX‐APOE mice. Overall, the experiments performed in JAX‐APOE mice validated findings from APOE ‐TR mice, identifying particularly strong effects of APOE4 genotype on lower APOE protein levels and simplified neuron structure. These data demonstrate pathways that could promote susceptibility of APOE4 brains to AD pathological changes. image

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  • Murine data in targeted replacement APOE mice and APOE knock-in mice support this observation, wherein reduced brain ApoE level and reduced basal dendritic spine density in the entorhinal cortex were found in ApoE4 mice compared with ApoE3 mice.

    “The murine data in targeted replacement APOE mice and APOE knock-in mice support this observation, wherein reduced brain ApoE level and reduced basal dendritic spine density in the entorhinal cortex were found in ApoE4 mice compared with ApoE3 mice [49].”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [49]

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Cited by

Sorted by citations

Authors
Sepulveda, J., Luo, N., Nelson, M., Ng, C. A. S., & Rebeck, G. W.
Affiliations
Georgetown University Medical Center (US)
Corresponding author
Rebeck, George William
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2022-07-29
Volume
163
Issue
3
Pages
247-259
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.15665
PMC
PMC9613529
OpenAlex
W4285490761
Cited by
24
References
13
Citations by year
2026: 9 · 2025: 5 · 2024: 5 · 2023: 5
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01 AG067258‐02, R01 NS100704‐05, R01 NS100704‐S2)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
APOE ε4, Alzheimer's disease, neuroinflammation, alpha-1-antichymotrypsin, interleukin-3, dendritic spines, entorhinal cortex, ibuprofen, learning and memory, mouse model validation
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Dendritic Spines, Mice, Apolipoprotein E3, Apolipoprotein E4

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