Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Abstract
JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.
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Transgenic mice expressing human tau with the P301L frontotemporal dementia mutation develop neurofibrillary tangles when coexpressing an FAD mutant APP transgene or after injection with Aβ42, indicating that Aβ42 promotes tangle formation.
“Transgenic mice expressing human tau with the P301L frontotemporal dementia mutation develop neurofibrillary tangles when coexpressing an FAD mutant APP transgene (Lewis et al., 2001; Oddo et al., 2003) or after injection with A 𝛃 42 (Gotz et al., 2001), indicating that A 𝛃 42 promotes tangle formation.”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Lewis et al., 2001
Findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP.
“These findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP [7,8,9,10,11,12,13,36].”
From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [11]
Aβ leads to exacerbated tau pathologies in mouse models expressing a tauopathy-related mutant tau gene.
“Several mouse modelling studies have shown that Aβ leads to exacerbated tau pathologies in mouse models expressing a tauopathy-related mutant tau gene (3, 4).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [3]
Prior studies showed that either co-expressing APP and MAPT genes or using prion-like seeding paradigms led to exacerbated Aβ and tau pathologies.
“Previous studies have shown that either co-expressing APP and MAPT genes (3, 6, 23) or using prion-like seeding paradigms (4, 24, 25) led to exacerbated Aβ and tau pathologies.”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [3]
Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis that lies upstream of tau-induced neurodegeneration.
“Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”
Mice expressing mutated human APP and mutated human tau develop several-fold increased neurofibrillary tangles compared with mice expressing only mutated human tau.
“Mice expressing mutated human APP and mutated human tau develop several-fold increased neurofibrillary tangles, compared with mice expressing only mutated human tau (Lewis et al., 2001).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Lewis et al., 2001
NFTs readily form in transgenic mice that express human tau containing mutations associated with FTLD; the most commonly used models express 4R tau with P301L or P301S mutations.
“In contrast, NFTs readily form in transgenic mice that express human tau containing mutations associated with FTLD; the most commonly used models being those that express 4R tau with P301L or P301S mutations[49, 91, 92, 135, 177].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [91]
A limited number of studies have reported animal models that display both plaques and tangles.
“A limited number of studies have reported the development of animal models that display both plaques and tangles [10, 51, 91, 109, 121].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [91]
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- Authors
- Lewis, J., Dickson, D. W., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S.-H., Sahara, N., Skipper, L., Yager, D., Eckman, C., Hardy, J., Hutton, M., & McGowan, E.
- Affiliations
- Mayo Clinic (US)
- Venue
- Science
- Published
- 2001-08-24
- Volume
- 293
- Issue
- 5534
- Pages
- 1487-1491
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2110888808
- Cited by
- 1,611
- References
- 35
- Citations by year
- 2026: 14 · 2025: 39 · 2024: 51 · 2023: 32 · 2022: 59 · 2021: 55 · 2020: 73 · 2019: 61 · 2018: 59 · 2017: 62 · 2016: 70 · 2015: 56 · 2014: 61 · 2013: 61 · 2012: 64
- FWCI
- 52.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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
- neurofibrillary tangles, tau protein, amyloid precursor protein, amyloid-beta, Tg2576 mice, double transgenic mice, Alzheimer's disease, limbic system, olfactory cortex, motor disturbances
- MeSH terms
- Alzheimer Disease, Animals, Brain, Crosses, Genetic, Disease Models, Animal, Female, Limbic System, Male, Mice, Transgenic, Mutation, Nerve Degeneration, Neurons, Peptide Fragments, RNA, Messenger, Sex Characteristics, Solubility, Spinal Cord, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Neurofibrillary Tangles, tau Proteins, Mice, Plaque, Amyloid
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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.
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