Cited by 332Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Temporal and regional progression of Alzheimer’s disease‐like pathology in 3xTg‐AD mice

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Belfiore, Ramona, Rodin, Alexis, Ferreira, Eric, Velazquez, Ramon, Branca, Caterina, Caccamo, Antonella, Oddo, Salvatore·2019·Aging Cell

Abstract

Accumulation of amyloid‐β (Aβ) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer’s disease (AD). After almost 15 years from their generation, 3xTg‐AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg‐AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed Aβ and tau load, neuroinflammation, and cognitive changes in 2‐, 6‐, 12‐, and 20‐month‐old female 3xTg‐AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had Aβ plaques in the caudal hippocampus at 6 months of age, while 100% of them had Aβ plaques in the hippocampus at 12 months of age. Cortical Aβ plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6‐month‐old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6‐month‐old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD‐like pathology in female 3xTg‐AD mice, and will facilitate the design of future studies using these mice.

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  • Cognitive impairment manifests at the age of 3 to 4 months in the 3×Tg-AD model.

    “Cognitive impairment manifests at the age of 3 to 4 months.”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Belfiore et al., 2019

    The Abstract says cognitive decline in the female 3xTg-AD mice studied was first apparent at 6 months, not 3–4 months. The Results section, “Learning and memory impairments in 3xTg-AD mice” (page unavailable), reports significant deficits at 6 months; the study tested mice at 2 and 6 months but not at 3–4 months. (LLM, conf=0.88)

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  • In 3xTg-AD mice, both Aβ and tau exhibit age- and region-dependent formation, with Aβ plaques appearing prior to tangles, which are extensive in older transgenic mice.

    “Both Aβ and tau exhibit age- and region-dependent formation in these mice, with Aβ plaques appearing prior to tangles, which are extensive in older transgenic mice.”

    From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [6]

    The Results sections on plaque accumulation and tau pathology (page unavailable) show age- and region-dependent changes in female 3xTg-AD mice: plaques first appear in the hippocampus at 6 months, and phosphorylated-tau immunoreactivity becomes extensive there at 12 and 20 months. The paper measures phosphorylated tau, not the formation or extent of tangles, so it does not establish that plaques appeared before tangles or that tangles were extensive in older mice. (LLM, conf=0.86)

    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 [6]

    The Results sections on plaques and tau pathology document age-dependent, region-specific progression, and the Discussion describes a consistent, predictable phenotype in female 3xTg-AD mice. The claim leaves that qualification out: the Animals section says only females were analyzed because males in this colony showed substantial neuropathological variability, and the Introduction notes differences among sublines. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • 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 [6]

    The Results sections on plaque accumulation and tau pathology report both pathologies in 12- and 20-month-old 3xTg-AD mice, with significant age-dependent increases in immunoreactivity. The paper studied 2-, 6-, 12-, and 20-month-old mice, not 15-month-old mice, so it does not directly establish the claim at that age. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • In the 3×Tg-AD model, tau pathology becomes detectable around 6 months of age, and neurofibrillary tangles appear after 12 months.

    “Tau pathology becomes detectable around 6 months of age, and neurofibrillary tangles appear after 12 months (Belfiore et al., 2019).”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Belfiore et al., 2019

    The Results section reports detectable tau phosphorylation in the hippocampus of female 3xTg-AD mice at 6 months. It does not establish that neurofibrillary tangles first appear after 12 months; the age-related findings concern phosphorylated-tau immunoreactivity, not tangle formation (page not provided). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Belfiore, R., Rodin, A., Ferreira, E., Velazquez, R., Branca, C., Caccamo, A., & Oddo, S.
Affiliations
  • University of Catania (IT)
  • Arizona State University (US)
  • The Arizona State University‐Banner Neurodegenerative Disease Research Center at the Biodesign Institute Arizona State University Tempe Arizona
Corresponding author
Oddo, Salvatore
Venue
Aging Cell
Publisher
Wiley
Published
2018-11-28
Volume
18
Issue
1
Pages
e12873-e12873
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
OpenAlex
W2902887888
Cited by
332
References
13
Citations by year
2026: 45 · 2025: 52 · 2024: 54 · 2023: 42 · 2022: 49 · 2021: 47 · 2020: 26 · 2019: 16 · 2018: 1
FWCI
15.47
Type
journal article
Language
en
Open access
Locations
  • Aging Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (RF1AG037637)
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, 3xTg-AD mice, amyloid plaques, tau phosphorylation, neuroinflammation, cognitive decline, hippocampus, entorhinal cortex, transgenic mouse model, disease progression, female mice
MeSH terms
Aging, Alzheimer Disease, Animals, Gliosis, Hippocampus, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Time Factors, Amyloid beta-Peptides, tau Proteins, Microglia, Disease Progression, Plaque, Amyloid

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