Tau filament formation in transgenic mice expressing P301L tau
Open accessAbstract
Mutations in the microtubule-associated protein tau, including P301L, are genetically coupled to hereditary frontotemporal dementia with parkinsonism linked to chromosome 17. To determine whether P301L is associated with fibril formation in mice, we expressed the longest human tau isoform, human tau40, with this mutation in transgenic mice by using the neuron-specific mouse Thy1.2 promoter. We obtained mice with high expression of human P301L tau in cortical and hippocampal neurons. Accumulated tau was hyperphosphorylated and translocated from axonal to somatodendritic compartments and was accompanied by astrocytosis and neuronal apoptosis indicated by terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end-labeling staining. Moreover, P301L tau formed abnormal filaments. Electron microscopy of sarcosyl-insoluble protein extracts established that the filaments had a straight or twisted structure of variable length and were approximately 15 nm wide. Immunoelcecton microscopy showed that the tau filaments were phosphorylated at the TG3, AT100, AT8, and AD199 epitopes in vivo. In cortex, brain stem, and spinal cord, neurofibrillary tangles were also identified by thioflavin-S fluorescent microscopy and Gallyas silver stains. Together, our results show that expression of the P301L mutation in mice causes neuronal lesions that are similar to those seen in human tauopathies.
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Transgenic mice expressing human mutated tau showed NFT formation and neuronal loss, implying a causal relationship between tau over-expression and neurodegeneration.
“transgenic mice expressing human mutated tau showed NFT formation and neuronal loss, implying a causal relationship between tau over-expression and neurodegeneration (8 -11).”
From CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy (2012) · cites this paper as [8]
The Abstract reports neurofibrillary tangles in mice expressing human P301L tau, and the Results report cortical neurons undergoing apoptosis. The paper does not demonstrate neuronal loss in the mice; its Discussion mentions severe neuronal loss in human patients instead. It links the mouse pathology to the P301L mutation in combination with high expression, not to tau overexpression alone. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGenetic studies show that the development of neurodegenerative tauopathies is associated with missense mutations in the microtubule-associated tau protein (MAPT).
“Genetic studies show that the development of neurodegenerative tauopathies is associated with missense mutations in the microtubule-associated tau protein (MAPT) [26].”
From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [26]
Both TASTPM and P301L mouse models are known to demonstrate a proinflammatory phenotype.
“Both mouse models are known to demonstrate a proinflammatory phenotype (17, 18).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [17]
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- Authors
- Götz, J., Chen, F., Barmettler, R., & Nitsch, R. M.
- Affiliations
- University of Zurich (CH)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 276
- Issue
- 1
- Pages
- 529-534
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2035156043
- Cited by
- 495
- References
- 26
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 29 · 2023: 13 · 2022: 20 · 2021: 18 · 2020: 16 · 2019: 17 · 2018: 9 · 2017: 16 · 2016: 10 · 2015: 11 · 2014: 15 · 2013: 22 · 2012: 18
- FWCI
- 18.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- transgenic mice, tau hyperphosphorylation, neurofibrillary tangles, tauopathy, neuronal apoptosis, astrocyte activation
- MeSH terms
- Animals, Brain, Gliosis, Humans, Immunohistochemistry, Mice, Transgenic, Actin Cytoskeleton, Microscopy, Electron, Microscopy, Fluorescence, Mutation, Organ Specificity, Phosphorylation, Protein Conformation, Immunoblotting, Gene Expression, Neurofibrillary Tangles, tau Proteins, Apoptosis, Amino Acid Substitution, Protein Isoforms, In Situ Nick-End Labeling, Mice
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