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Cited by 72Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer's disease pathology in APOE transgenic mouse models: The Who, What, When, Where, Why, and How

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Lewandowski, Cutler T., Maldonado Weng, Juan, LaDu, Mary Jo·2020·Neurobiology of Disease
DOI 10.1016/j.nbd.2020.104811PMC PMC7150653
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Abstract

The focus on amyloid plaques and neurofibrillary tangles has yielded no Alzheimer's disease (AD) modifying treatments in the past several decades, despite successful studies in preclinical mouse models. This inconsistency has caused a renewed focus on improving the fidelity and reliability of AD mouse models, with disparate views on how this improvement can be accomplished. However, the interactive effects of the universal biological variables of AD, which include age, APOE genotype, and sex, are often overlooked. Age is the greatest risk factor for AD, while the ε4 allele of the human APOE gene, encoding apolipoprotein E, is the greatest genetic risk factor. Sex is the final universal biological variable of AD, as females develop AD at almost twice the rate of males and, importantly, female sex exacerbates the effects of APOE4 on AD risk and rate of cognitive decline. Therefore, this review evaluates the importance of context for understanding the role of APOE in preclinical mouse models. Specifically, we detail how human AD pathology is mirrored in current transgenic mouse models ("What") and describe the critical need for introducing human APOE into these mouse models ("Who"). We next outline different methods for introducing human APOE into mice ("How") and highlight efforts to develop temporally defined and location-specific human apoE expression models ("When" and "Where"). We conclude with the importance of choosing the human APOE mouse model relevant to the question being addressed, using the selection of transgenic models for testing apoE-targeted therapeutics as an example ("Why").

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  • A hallmark of the ApoE4 mouse phenotype is reduced neuronal complexity, characterized by fewer, shorter, and less branched dendrites, including reduced dendritic spine density in the hippocampus and entorhinal cortex.

    “A hallmark of the ApoE4 mouse phenotype is reduced neuronal complexity, characterized by fewer, shorter, and less branched dendrites. This includes a major reduction in dendritic spine density in the hippocampus (specifically the dentate gyrus and CA1 regions) and the entorhinal cortex [26–28].”

    From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [26]

    The ‘APOE Transgenic Mice’ section says APOE-targeted replacement mice show isoform-dependent changes in synaptic number and structure, and the References list a study of reduced spine density and dendritic complexity in cortical neurons. Our copy does not substantiate fewer or shorter dendrites, a major reduction in spine density, or the specified hippocampal and entorhinal regions. (LLM, conf=0.82)

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Authors
Lewandowski, C. T., Maldonado Weng, J., & LaDu, M. J.
Affiliations
University of Illinois Chicago (US)
Corresponding author
LaDu, Mary Jo
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2020-06
Volume
139
Pages
104811
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2020.104811
PMC
PMC7150653
OpenAlex
W3007464392
Cited by
72
References
73
Citations by year
2026: 3 · 2025: 9 · 2024: 19 · 2023: 7 · 2022: 13 · 2021: 17 · 2020: 4
FWCI
1.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • American Heart 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
Alzheimer's disease, apolipoprotein E, APOE ε4, amyloid plaques, neurofibrillary tangles, sex differences, age effects, model selection, cognitive decline
MeSH terms
Alleles, Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Female, Genotype, Humans, Male, Mice, Transgenic, Reproducibility of Results, Amyloid beta-Peptides, tau Proteins, Mice, Apolipoprotein E4, Plaque, Amyloid, Cognitive Dysfunction

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