Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice
Open accessAbstract
Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aβ pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PS1 and tau mutations (5xFAD×Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD×Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD×Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD×Tg30 than in Tg30 mice. Extracellular amyloid load, Aβ40 and Aβ42, β-CTFs and β-CTF phosphorylation levels were lower in 5xFAD×Tg30 mice than in 5xFAD mice. Despite this reduction of Aβ, a significant hippocampal neuronal loss was observed in 5xFAD×Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD×Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional post-translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of Aβ pathology.
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In 5xFAD/Tg30 mice, a loss of ~25% of pyramidal neurons in the hippocampus (CA1-CA4) was detected in 9-month-old mice, while no difference was detected in WT, 5xFAD, or Tg30 mice.
“While no difference in the number of pyramidal neurons in the hippocampus (CA1–CA4) was detected in either 9-month-old WT, 5xFAD, or Tg30 mice, a loss of ~25% of pyramidal neurons in this area was detected in age-matched 5xFAD/Tg30 mice [60].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [60]
Crossing transgenic APP mouse over-expression models with tau mouse models generally shows that Aβ accelerates tau pathology.
“The results generally show that Aβ accelerates tau pathology (Chabrier et al., 2014; Heraud et al., 2014; Stancu et al., 2014; Chen et al., 2016).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Heraud et al., 2014
The tau pathology does not appear to increase Aβ deposition.
“The tau pathology does not appear to increase Aβ deposition (Saul et al., 2013; Chabrier et al., 2014; Heraud et al., 2014; Stancu et al., 2014; Chen et al., 2016; Kang et al., 2021); indeed, in some cases it accelerates removal of Aβ (Chen et al., 2016).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Heraud et al., 2014
Our results for Aβ and MAPT pathologies are generally consistent with prior observations using crosses of APP over-expression mouse lines and MAPT over-expression mouse models.
“Our results for Aβ and MAPT pathologies are generally consistent with prior observations using crosses of APP over-expression mouse lines and MAPT over-expression mouse models (Saul et al., 2013; Chabrier et al., 2014; Heraud et al., 2014; Stancu et al., 2014; Chen et al., 2016; Kang et al., 2021).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Heraud et al., 2014
The same studies indicate that the presence of MAPT pathology either does not change the accumulation of Aβ pathology or decreases it.
“These same studies indicate that the presence of MAPT pathology either does not change the accumulation of Aβ pathology or decreases it (Saul et al., 2013; Chabrier et al., 2014; Heraud et al., 2014; Stancu et al., 2014; Chen et al., 2016; Kang et al., 2021), with only one initial study suggesting that MAPT pathology increases Aβ pathology (Ribe et al., 2005).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Heraud et al., 2014
Over-expression models consistently observe that the presence of Aβ pathology enhances the accumulation of MAPT pathology, neurodegeneration and cognitive loss.
“These over-expression models consistently observe that the presence of Aβ pathology enhances the accumulation of MAPT pathology, neurodegeneration and cognitive loss (Saul et al., 2013; Chabrier et al., 2014; Heraud et al., 2014; Stancu et al., 2014; Chen et al., 2016; Kang et al., 2021).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Heraud et al., 2014
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 [13]
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References 47 · Cited by 80
- Authors
- Héraud, C., Goufak, D., Ando, K., Leroy, K., Suain, V., Yilmaz, Z., De Decker, R., Authelet, M., Laporte, V., Octave, J.-N., & Brion, J.-P.
- Affiliations
- Université Libre de Bruxelles (BE)
- UCLouvain (BE)
- Corresponding author
- Brion, Jean-Pierre
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 62
- Pages
- 100-112
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W1985259299
- Cited by
- 80
- References
- 47
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 12 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 8 · 2014: 5
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- green
- dipot.ulb.ac.be
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Diane program (Walloon region) (816856)
- Fonds de la Recherche Scientifique Médicale (3.4504.10)
- 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
- tau misfolding, tau truncation, neurofibrillary tangles, amyloid-beta, tau phosphorylation, PHF-tau, neuronal loss, Alzheimer's disease, tauopathy, motor phenotype
- MeSH terms
- Age Factors, Animals, Cerebral Cortex, Hippocampus, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Phosphorylation, Spinal Cord, Survival Rate, Amyloid beta-Protein Precursor, tau Proteins, Protein Folding, Pyramidal Cells, Mice, Presenilin-1, Plaque, Amyloid
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