Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein
Abstract
Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.
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Several invertebrate and vertebrate transgenic animal models have shown that tau can induce neurodegeneration and apoptosis.
“Several invertebrate and vertebrate transgenic animal models have shown that tau can induce neurodegeneration and apoptosis (43–46).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [44]
JNPL3 mice express human tau carrying the FTDP-17 mutation P301L (tauP301L).
“JNPL3 mice express human tau carrying the FTDP-17 mutation P301L (tauP301L).”
From Tau promotes neurodegeneration through global chromatin relaxation (2014) · cites this paper as [35]
JNPL3 tau transgenic mice undergo progressive neurodegeneration and develop neurofibrillary tangles in the brain and spinal cord.
“These tau transgenic mice undergo progressive neurodegeneration, and develop neurofibrillary tangles in the brain and spinal cord35.”
From Tau promotes neurodegeneration through global chromatin relaxation (2014) · cites this paper as [35]
Mouse models over-expressing WT or mutant tau exhibit progressive neurodegeneration.
“These models also exhibit progressive neurodegeneration, which is consistent with observations in humans that cognitive loss is more closely associated with tau pathology than Aβ pathology (Lewis et al., 2000; Ramsden et al., 2005; Polydoro et al., 2009).”
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 Lewis et al., 2000
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).”
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- Authors
- Lewis, J., McGowan, E., Rockwood, J., Melrose, H., Nacharaju, P., Van Slegtenhorst, M., Gwinn-Hardy, K., Murphy, M. P., Baker, M., Yu, X., Duff, K., Hardy, J., Corral, A., Lin, W.-L., Yen, S.-H., Dickson, D. W., Davies, P., & Hutton, M.
- Affiliations
- Mayo Clinic (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Hutton, Mike
- ORCID
- Venue
- Nature Genetics
- Published
- 2000-08
- Volume
- 25
- Issue
- 4
- Pages
- 402-405
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1480786153
- Cited by
- 1,371
- References
- 1
- Citations by year
- 2026: 30 · 2025: 36 · 2024: 36 · 2023: 43 · 2022: 57 · 2021: 54 · 2020: 59 · 2019: 47 · 2018: 63 · 2017: 47 · 2016: 49 · 2015: 54 · 2014: 54 · 2013: 59 · 2012: 55
- FWCI
- 27.93
- Type
- journal article
- Language
- en
- Update notices
- erratum (2000-09-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- U.S. Public Health Service
- 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
- neurofibrillary tangles, tau protein, P301L mutation, FTDP-17, tauopathy, transgenic mice, amyotrophy, motor disturbances, Pick bodies, reactive gliosis, peripheral neuropathy, Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia
- MeSH terms
- Animals, Brain Stem, Cell Count, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Movement Disorders, Mutation, Neurons, Spinal Cord, Gene Expression, Neurofibrillary Tangles, tau Proteins, Muscle, Skeletal, Amino Acid Substitution, Brachial Plexus Neuritis, Mice
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