The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy
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We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation deltaK280 (Tau(RD)/deltaK280), or the deltaK280 plus two proline mutations in the hexapeptide motifs (Tau(RD)/deltaK280/I277P/I308P). The deltaK280 mutation accelerates aggregation ("proaggregation mutant"), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models ("antiaggregation mutant"). The inducible transgene expression was driven by the forebrain-specific CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2-3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [KXGS motifs, targets of the kinase MARK (microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human…
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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 Mocanu et al., 2008
Expression of mutant tau in mouse models of Alzheimer's disease-like tau neuropathologies can result in a significant loss of dendritic spines and synapses.
“Significantly, the expression of mutant tau in mouse models of Alzheimer’s disease-like tau neuropathologies can result in a significant loss of dendritic spines and synapses (Mocanu et al., 2008; Bittner et al., 2010; Rocher et al., 2010).”
From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Mocanu et al., 2008
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- Authors
- Mocanu, M.-M., Nissen, A., Eckermann, K., Khlistunova, I., Biernat, J., Drexler, D., Petrova, O., Schönig, K., Bujard, H., Mandelkow, E., Zhou, L., Rune, G., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Heidelberg University (DE)
- Universität Hamburg (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-01-16
- Volume
- 28
- Issue
- 3
- Pages
- 737-748
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6670355
- OpenAlex
- W2167937350
- Cited by
- 297
- References
- 9
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 15 · 2023: 19 · 2022: 6 · 2021: 16 · 2020: 19 · 2019: 12 · 2018: 20 · 2017: 18 · 2016: 13 · 2015: 15 · 2014: 14 · 2013: 22 · 2012: 26
- FWCI
- 16.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, tauopathy, tau repeat domain, beta-structure, FTDP-17, proline mutations, tau aggregation, transgenic mouse model, inducible transgene expression, hyperphosphorylation, MARK kinases, synaptic loss, neuronal loss, astrocyte activation, tau tangles, Alzheimer's disease
- MeSH terms
- Age Factors, Animals, Detergents, Disease Models, Animal, Humans, Mice, Transgenic, Mutation, Neurons, Phosphorylation, Sarcosine, Synapses, Gene Expression, Silver Staining, Neurofibrillary Tangles, tau Proteins, Cell Death, Protein Structure, Tertiary, Tauopathies, Microscopy, Electron, Transmission, Mice
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