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The role of APOE in transgenic mouse models of AD

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Balu, Deebika, Karstens, Aimee James, Loukenas, Efstathia, Maldonado Weng, Juan, York, Jason M., Valencia-Olvera, Ana Carolina, LaDu, Mary Jo·2019·Neuroscience Letters
DOI 10.1016/j.neulet.2019.134285PMC PMC6717006
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Abstract

Identified in 1993, APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to the common variant APOE3. Since the mid 1990's, transgenic (Tg) mice have been developed to model AD pathology and progression, primarily via expression of the familial AD (FAD) mutations in the presence of mouse-APOE (m-APOE). APOE4, associated with enhanced amyloid-β (Aβ) accumulation, has rarely been the focus in designing FAD-Tg mouse models. Initially, FAD-Tg mice were crossed with human (h)-APOE driven by heterologous promoters to identify an APOE genotype-specific AD phenotype. These models were later supplemented with FAD-Tg mice crossed with APOE-knockouts (APOE-/- or APOE-KO) and h-APOE-targeted replacement (h-APOE-TR) mice, originally generated to study the role of APOE genotype in peripheral lipid metabolism and atherosclerotic lesion development. Herein, we compare the m- and h-APOE multi-gene clusters, and then critically review the relevant history and approaches to developing a Tg mouse model to characterize APOE-dependent AD pathology, in combination with genetic (sex, age) and modifiable (e.g., inflammation, obesity) risk factors. Finally, we present recent data from the EFAD mice, which express 5xFAD mutations with the expression of the human apoE isoforms (E2FAD, E3FAD and E4FAD). This includes a study of 6- and 18-month-old male and female E3FAD and E4FAD, a comparison that enables examination of the interaction among the main AD risk factors: age, APOE genotype and sex. While no single transgenic mouse can capture the effects of all modifiable and genetic risk factors, going forward, a conscious effort needs to be made to include the factors that most significantly modulate AD pathology.

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  • Both male and female E4FAD or APOE3+/+ mouse models with 5xFAD background (E3FAD) manifested with AD-related pathological, neuro-inflammatory, and behavioral phenotypes at 4-8 months of age, such as memory impairments measured by novel object recognition (NOR) tests with an inability to discriminate between novel and familiar objects.

    “It was previously demonstrated that both male and female E4FAD or APOE3+/+ mouse models with 5xFAD background (E3FAD) manifested with AD-related pathological, neuro-inflammatory, and behavioral phenotypes at 4–8 months of age [29, 30], such as memory impairments measured by novel object recognition (NOR) tests with an inability to discriminate between novel and familiar objects [49].”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [29]

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  • The 5xFAD model used in this study provided a model with well-characterized APOE-dependent changes in amyloid pathology.

    “Second, the 5xFAD model used in this study provided a model with well-characterized APOE-dependent changes in amyloid pathology55,63,64.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [64]

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Cited by

Sorted by citations

Authors
Balu, D., Karstens, A. J., Loukenas, E., Maldonado Weng, J., York, J. M., Valencia-Olvera, A. C., & LaDu, M. J.
Affiliations
University of Illinois Chicago (US)
Corresponding author
LaDu, Mary Jo
ORCID
Venue
Neuroscience Letters
Publisher
Elsevier BV
Published
2019-08
Volume
707
Pages
134285
ISSN
0304-3940 (ISSN-L)
DOI
10.1016/j.neulet.2019.134285
PMC
PMC6717006
OpenAlex
W2947805301
Cited by
81
References
26
Citations by year
2026: 7 · 2025: 13 · 2024: 24 · 2023: 10 · 2022: 7 · 2021: 12 · 2020: 5 · 2019: 2 · 2018: 1
FWCI
0.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience Letters (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health
  • Alzheimer's Association
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
APOE ε4, Alzheimer's disease, transgenic mouse model, familial Alzheimer's disease, amyloid-beta deposition, ApoE-deficient mice, targeted replacement mice, sex differences, age, modifiable risk factors, inflammation, obesity, lipid metabolism, atherosclerosis
MeSH terms
Age Factors, Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Female, Male, Mice, Transgenic, Mutation, Phenotype, Sex Factors, tau Proteins

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