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Cited by 203Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Systematic Phenotyping and Characterization of the 3xTg-AD Mouse Model of Alzheimer’s Disease

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Javonillo, Dominic I., Tran, Kristine M., Phan, Jimmy, Hingco, Edna, Kramár, Enikö A., da Cunha, Celia, Forner, Stefania, Kawauchi, Shimako +14 more·2022·Frontiers in Neuroscience
DOI 10.3389/fnins.2021.785276PMC PMC8818877

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Abstract

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimer’s disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in long-term potentiation followed by quantification of amyloid beta (Aβ) plaque burden and neurofibrillary tau tangles, biochemical levels of Aβ and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline and show plasma NfL is strongly driven by plaque burden. The results from these analyses are freely available via the AD Knowledge Portal ( https://modeladexplorer.org/ ). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD.

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  • Aβ plaque and tau pathology are evident in 15-month-old TG mice, and significantly increased with age.

    “In our morphological analysis (Fig. 2 and 3), as previously described [3–6, 28], Aβ plaque and tau pathology are evident in 15-month-old TG mice, and significantly increased with age (online supplementary Fig.1 and 2).”

    From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [28]

    The Results sections on fibrillar Aβ plaques and phosphorylated tau report age-related increases in 3xTg-AD mice. However, the paper examines mice at 4, 12, and 18 months—not 15 months—and says plaque accumulation is largely driven by females, so it does not establish the claim at the stated age for TG mice generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The 3xTg-AD mouse provides a robust model of Alzheimer's disease with region-dependent patterns of progressive amyloid-β and tau pathology.

    “The widely studied triple transgenic (3xTg-AD) mouse provides a robust model of Alzheimer’s disease (AD) with region dependent patterns of progressive amyloid-β (Aß) and tau pathology.”

    From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [28]

  • One representative brain slice from each mouse within identical experimental cohort was subjected to simultaneous staining in the same container.

    “One representative brain slice from each mouse within the identical experimental cohort (comprising the same genotype, age, and sex) was subjected to simultaneous staining in the same container as described [25, 27].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [27]

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Authors
Javonillo, D. I., Tran, K. M., Phan, J., Hingco, E., Kramár, E. A., da Cunha, C., Forner, S., Kawauchi, S., Milinkeviciute, G., Gomez-Arboledas, A., Neumann, J., Banh, C. E., Huynh, M., Matheos, D. P., Rezaie, N., Alcantara, J. A., Mortazavi, A., Wood, M. A., Tenner, A. J., MacGregor, G. R., Green, K. N., & LaFerla, F. M.
Affiliations
University of California, Irvine (US)
Corresponding author
  • Green, Kim N.
  • LaFerla, Frank M.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2022-01-24
Volume
15
Pages
785276-785276
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2021.785276
PMC
PMC8818877
OpenAlex
W4211205244
Cited by
203
References
34
Citations by year
2026: 36 · 2025: 41 · 2024: 62 · 2023: 48 · 2022: 15 · 2021: 1
FWCI
25.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging
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
3xTg-AD mice, Alzheimer's disease, animal model characterization, amyloid plaques, neurofibrillary tangles, long-term potentiation, gliosis, dystrophic neurites, neurofilament light chain, plasma biomarkers, plaque burden, model drift, deep phenotyping

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