Temporal and regional progression of Alzheimer’s disease‐like pathology in 3xTg‐AD mice
Open accessAbstract
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)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn 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 measuredThe 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 measuredAβ 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 measuredIn 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
By 12 months of age, amyloid-beta deposits have spread extensively from the caudal hippocampus to other regions in the 3×Tg-AD model.
“By 12 months of age, Aβ deposits have spread extensively from the caudal hippocampus to other regions (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 (page unavailable) reports plaques first in the caudal hippocampus, in all three hippocampal regions by 12 months, and first detectable in several cortical regions at 12 months. Calling the spread “extensive” by that age overstates the finding: the paper says plaques were present throughout the cortex at 20 months. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the 3×Tg-AD model, intraneuronal amyloid-beta begins accumulating around 2 months of age while extracellular amyloid-beta deposits become apparent at 6 months.
“intraneuronal Aβ begins accumulating around 2 months of age while extracellular Aβ deposits become apparent at 6 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 Results section on age-dependent plaque accumulation (page unavailable) reports that extracellular Aβ plaques were absent at 2 months and first detected in the hippocampus at 6 months. It does not establish that intraneuronal Aβ begins accumulating around 2 months; a search for “intraneuronal” found no passage reporting that onset. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAt around 9 months in the 3×Tg-AD model, neuroinflammation becomes evident and amyloid-beta deposition shifts from intraneuronal to extracellular.
“It is at this specific stage that neuroinflammation becomes evident and Aβ deposition shifts from intraneuronal to extracellular (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 sections on microgliosis and Aβ plaques report that microglial activation and extracellular plaques were first detected at 6 months in female 3xTg-AD mice, supporting the general progression described. The paper does not establish a shift from intraneuronal to extracellular deposition at around 9 months; it did not assess a 9-month group. (LLM, conf=0.87)
Experimental — accuracy not yet measured3xTg-AD mice are one of the only models to develop both Aβ plaques and NFTs, in addition to exhibiting stark sexual dimorphism.
“They are one of the only models to develop both Aβ plaques and NFTs, in addition to exhibiting stark sexual dimorphism [18–22].”
From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [22]
The Introduction says 3xTg-AD mice accumulate plaques and tangles, and the Discussion contrasts their Aβ and tau pathology with that of most other mouse models. The Animals section says only females were studied because males in this colony showed substantial neuropathological variability; it does not establish stark sexual dimorphism through a male–female comparison. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe 3xTg-AD mouse develops both amyloid-β and neurofibrillary tangles in a temporal and spatial pattern similar to human AD pathology.
“It develops both amyloid-β (Aβ) and neurofibrillary tangles in a temporal and spatial pattern similar to human AD pathology [3–6].”
From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [6]
Due to the variability of the degree of AD pathology described in this model, large ROIs, as used for the HD and HV, may have attenuated some effects.
“Additionally, due to the variability of the degree of AD pathology described in this model [4, 6, 26], large ROIs, as used for the HD and HV, may have attenuated some effects.”
From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [6]
The 3×Tg-AD model exhibits both amyloid-beta accumulation and neurofibrillary tangles following a temporal and spatial pattern similar to that observed in human Alzheimer's disease.
“This model exhibits both Aβ accumulation and neurofibrillary tangles following a temporal and spatial pattern similar to that observed in human AD (Bloom, 2014; 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
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- 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
- PMC
- PMC6351836
- 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
- gold
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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