The β-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy
Open accessAbstract
Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a beta-structure conformation and hence to aggregate. The "pro-aggregation" mutant DeltaK280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant DeltaK280/PP cannot aggregate because of two beta-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the anti-aggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The absence of robust MAPT pathology in mouse models expressing only endogenous MAPT likely derives from the low aggregation propensity of murine MAPT.
“The absence of robust MAPT pathology in mouse models expressing only endogenous MAPT likely derives from the low aggregation propensity of murine MAPT (Eckermann et al., 2007; Mocanu et al., 2008).”
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 Eckermann et al., 2007
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
Gossen, M., & Bujard, H. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5547 · Cited by 4,943 · see citing works
Self-citationTriple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · see citing works
Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., & Sabatini, B. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4970-06.2007 · Cited by 1,592 · see citing works
Köpke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., & Grundke-Iqbal, I. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80536-5 · Cited by 779 · see citing works
Tau filament formation in transgenic mice expressing P301L tau
Götz, J., Chen, F., Barmettler, R., & Nitsch, R. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006531200 · Cited by 495 · see citing works
Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404
Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., & Lee, V. M. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490390607 · Cited by 488 · see citing works
Synaptic slaughter in Alzheimer's disease
Coleman, P. (2003) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.09.001 · Cited by 351 · see citing works
Andreadis, A. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.08.010 · Cited by 311 · see citing works
Hirokawa, N., Funakoshi, T., Sato-Harada, R., & Kanai, Y. (1996) · The Journal of cell biology · doi:10.1083/jcb.132.4.667 · Cited by 179 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- Weingarten, M. D., Lockwood, A. H., Hwo, S. Y., and Kirschner, M. W. (1975) Proc. Natl. Acad. Sci. U. S. A. 72, 1858 -1862
- von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E. M., and Mandelkow, E. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 5129 -5134
- Greenberg, S. G., and Davies, P. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 5827-5831
- Gossen, M., and Bujard, H. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 5547-5551
Cited by
Sorted by citations
Tau protein liquid–liquid phase separation can initiate tau aggregation
Wegmann, S., Eftekharzadeh, B., Tepper, K., Zoltowska, K. M., Bennett, R. E., Dujardin, S., Laskowski, P. R., MacKenzie, D., Kamath, T., Commins, C., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201798049 · Cited by 1,102 · see citing works
Self-citationHoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.030 · Cited by 1,118 · see citing works
The importance of tau phosphorylation for neurodegenerative diseases
Noble, W., Hanger, D. P., Miller, C. C. J., & Lovestone, S. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00083 · Cited by 475 · see citing works
Sydow, A., Van der Jeugd, A., Zheng, F., Ahmed, T., Balschun, D., Petrova, O., Drexler, D., Zhou, L., Rune, G., Mandelkow, E., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5245-10.2011 · Cited by 302 · see citing works
Self-citationHyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability
Alonso, A. D., Cohen, L. S., Corbo, C., Morozova, V., ElIdrissi, A., Phillips, G., & Kleiman, F. E. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00338 · Cited by 278 · see citing works
Soluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
A role for tau at the synapse in Alzheimer’s disease pathogenesis
Pooler, A. M., Noble, W., & Hanger, D. P. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.018 · Cited by 203 · see citing works
Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau
Van der Jeugd, A., Hochgräfe, K., Ahmed, T., Decker, J. M., Sydow, A., Hofmann, A., Wu, D., Messing, L., Balschun, D., D’Hooge, R., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-0987-3 · Cited by 135 · see citing works
Self-citationSong, H.-L., Kim, N.-Y., Park, J., Kim, M. I., Jeon, Y.-N., Lee, S.-J., Cho, K., Shim, Y.-L., Lee, K.-H., Mun, Y.-S., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci156537 · Cited by 26 · see citing works
Jiang, L., Roberts, R., Wong, M., Zhang, L., Webber, C. J., Libera, J., Wang, Z., Kilci, A., Jenkins, M., Ortiz, A. R., et al. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1372297 · Cited by 15 · see citing works
- Authors
- Eckermann, K., Mocanu, M.-M., Khlistunova, I., Biernat, J., Nissen, A., Hofmann, A., Schönig, K., Bujard, H., Haemisch, A., Mandelkow, E., Zhou, L., Rune, G., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Heidelberg University (DE)
- Universität Hamburg (DE)
- Corresponding author
- Mandelkow, Eva-Maria
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 282
- Issue
- 43
- Pages
- 31755-31765
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2129932730
- Cited by
- 168
- References
- 12
- Citations by year
- 2025: 6 · 2024: 8 · 2023: 13 · 2022: 3 · 2021: 11 · 2020: 14 · 2019: 7 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 8 · 2014: 13 · 2013: 8 · 2012: 12
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- Universität Hamburg
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tauopathy, neurofibrillary tangles, protein aggregation, proline mutations, frontotemporal dementia, transgenic mouse model, inducible gene expression, synaptic loss, hyperphosphorylation, reversible aggregation
- MeSH terms
- Animals, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Transgenic, Mutation, Phosphorylation, Protein Conformation, Synapses, tau Proteins, Protein Isoforms, Amino Acid Motifs, Tauopathies, Mice
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 ›
Are you an author, or do you see a problem with this page? Request a review
