Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease

Oddo, S

doi:10.1016/j.neurobiolaging.2003.08.012

Cited by 980Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease

Oddo, S·2003·Neurobiology of Aging

DOI 10.1016/j.neurobiolaging.2003.08.012

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Abstract

Amyloid-beta (Abeta) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer's disease (AD). To better mimic this neuropathology, we generated a novel triple transgenic model of AD (3xTg-AD) harboring three mutant genes: beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and tauP301L. The 3xTg-AD mice progressively develop Abeta and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Abeta deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human betaAPP and human tau transgenes, Abeta deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.

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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 [3]
The 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 [3]
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 [3]
3xTg-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 [18]
Aβ-induced cytokines promote tau hyperphosphorylation and pathology, creating a self-perpetuating loop that worsens disease.
“Similarly, Aβ-induced cytokines promote tau hyperphosphorylation and pathology, thus initiating a self-perpetuating loop that culminates in worsening disease44,45.”
From Microglia in neurodegeneration (2018) · cites this paper as [44]

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Authors: Oddo, S.
Affiliations: University of California, Irvine (US)
Corresponding author: Oddo, S
ORCID: Oddo, S
Venue: Neurobiology of Aging
Publisher: Elsevier BV
Published: 2003-12
Volume: 24
Issue: 8
Pages: 1063-1070
ISSN: 0197-4580 (ISSN-L)
DOI: 10.1016/j.neurobiolaging.2003.08.012
OpenAlex: W1977002082
Cited by: 980
References: 12
Citations by year: 2026: 16 · 2025: 31 · 2024: 56 · 2023: 33 · 2022: 47 · 2021: 37 · 2020: 49 · 2019: 47 · 2018: 46 · 2017: 44 · 2016: 38 · 2015: 42 · 2014: 50 · 2013: 62 · 2012: 54
FWCI: 10.37
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Aging (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
University of California, Irvine
National Institute on Aging (AG0212982, AG17968, R01AG017968)
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, amyloid-beta deposition, neurofibrillary tangles, tau pathology, triple transgenic mouse model, 3xTg-AD mice, amyloid hypothesis, amyloid precursor protein, presenilin 1, P301L tau, hippocampus, cortex
MeSH terms: Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Membrane Proteins, Mice, Transgenic, Mutation, Amyloid beta-Protein Precursor, Neurofibrillary Tangles, tau Proteins, Disease Progression, Mice, Presenilin-1, Plaque, Amyloid

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Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease

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