Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L)
Open accessAbstract
Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tau P301L )4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca 2+ calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tau P301L )4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation- and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tau P301L expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tau P301L )4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.
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In Tg4510 MAPT transgenics evaluated at 4 and 6 months, memory task impairment and neurodegenerative pathology correspond to sequential activation of neuronal and microglial expression patterns.
“in Tg4510 MAPT transgenics evaluated at 4 and 6 months, respectively, memory task impairment and neurodegenerative pathology correspond to sequential activation of neuronal and microglial expression patterns (Blackmore et al., 2017; Ramsden et al., 2005).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Ramsden et al., 2005
The Discussion reports significant spatial-memory deficits from 4.5 months, and the age-dependent neurodegeneration section reports significantly lower brain weights from 5 months in rTg(tau P301L)4510 mice. The paper does not establish that these changes correspond to sequential activation of neuronal and microglial expression patterns; that part of the jointly cited sentence is not supported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe general pattern of p-tau accumulation in PS19 mice matched recent reports of brain-wide p-tau accumulation in the P301L tauopathy model.
“The general pattern of p-tau accumulation matched recent reports of brain-wide p-tau accumulation in the P301L tauopathy model (Ramsden et al., 2005; Detrez et al., 2019).”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Ramsden et al., 2005
The ‘Pathological tau conformation and phosphorylation’ section reports age-dependent accumulation of phosphorylated tau in the cortex and hippocampus of rTg(tauP301L)4510 mice. Figure 1 and the Discussion describe expression as forebrain-restricted, so the paper supports accumulation across those regions but not the claim of brain-wide accumulation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMouse 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 Ramsden et al., 2005
The Discussion (pp. 10637–10647; passage page unspecified) describes progressive neurodegeneration and substantial neuron loss in the authors’ P301L tau mice. It also mentions cell death in a non-mutant human-tau model, but cautions that most earlier mutant-tau models did not exhibit or report brain neuron loss. The broad claim about mouse models overexpressing either form therefore goes beyond what this paper establishes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe rTg4510 mouse model specifically expresses tau in the forebrain without amyloid plaques.
“A mouse model of tauopathy (rTg4510) has been developed that specifically expresses tau in the forebrain but without amyloid plaques”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Ramsden et al., 2005
The Generation of transgenic mice section describes rTg4510 as a mutant human tau model and reports that transgenic tau expression was primarily restricted to the forebrain, especially the hippocampus and cortex (page not available). The passages searched for amyloid plaques do not report whether plaques were absent in these mice, so that part of the claim is not established by our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredFrom 2.5 months onward, phosphorylated tau protein and neuronal loss can be detected in the forebrain of rTg4510 mice.
“From 2.5 months onward, phosphorylated tau protein and neuronal loss can be detected in the forebrain of these mice (14,34,35).”
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 [34]
The Figure 2 caption reports phosphorylated-tau labeling in hippocampal neurons at 2.5 months. The age-dependent neurodegeneration section reports marked neuronal loss in 10-month-old mice, while the Discussion cites neuron counts at 5.5 months; neither establishes detectable neuronal loss from 2.5 months onward. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Mutant tau expression in rTg4510 mice starts around postnatal day 7 and peaks at 1 month of age.
“Mutant tau expression starts around postnatal day 7 and peaks at 1 month of age (34,35).”
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 [34]
The ‘Generation of transgenic mice expressing mutant human tau P301L’ section reports that transgenic tau was first detected at postnatal day 7, supporting the onset part of the claim. Neither that passage nor the Figure 1 caption states that expression peaks at one month; the caption identifies P7 as the earliest expression shown by the postnatal forebrain immunoblot. (LLM, conf=0.86)
Experimental — accuracy not yet measuredExpression of tau in the rTg4510 mouse is driven by a forebrain specific promoter (CaMKII).
“This is to be expected as expression of tau is driven by a forebrain specific promoter (CaMKII) in the rTg4510 mouse (Ramsden et al., 2005).”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Ramsden et al., 2005
The rTg4510 mouse mimics features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus.
“The rTg4510 mouse mimics the features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus (Ramsden et al., 2005, Santacruz et al., 2005).”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Ramsden et al., 2005
Histological studies have demonstrated deposition of NFTs pathology, in particular in the cortex and hippocampus, and marked atrophy of these areas.
“Histological studies have demonstrated deposition of NFTs pathology, in particular, in the cortex (CRX) and hippocampus and marked atrophy of these areas [27][28][29][30][31][32].”
From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [27]
In rTg4510 mice, age-dependent loss of neurons and progressive cognitive dysfunction closely mimic the clinical features of tauopathy.
“In rTg4510 mice (34,35), the age-dependent loss of neurons and progressive cognitive dysfunction closely mimic the clinical features of tauopathy.”
Substantial neurodegeneration is observed after 5 months of age in rTg4510 mice, being most apparent in the hippocampal CA1 area.
“Substantial neurodegeneration is observed after 5 months of age, being most apparent in the hippocampal CA1 area (14,34,35).”
In rTg4510 mice, tau with the P301L mutation is over-expressed in the forebrain driven by the CaMKII promoter.
“In rTg4510 mice (34,35), tau with the mis-sense mutation P301L, found in some FTDP-17 cases (36), is over-expressed in the forebrain driven by the calcium-calmodulin kinase II (CaMKII) promoter.”
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- Authors
- Ramsden, M., Kotilinek, L., Forster, C., Paulson, J., McGowan, E., SantaCruz, K., Guimaraes, A., Yue, M., Lewis, J., Carlson, G., Hutton, M., & Ashe, K. H.
- Affiliations
- University of Minnesota (US)
- Mayo Clinic (US)
- McLaughlin Research Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-11-16
- Volume
- 25
- Issue
- 46
- Pages
- 10637-10647
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725849
- OpenAlex
- W2107804537
- Cited by
- 702
- References
- 7
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 46 · 2023: 61 · 2022: 49 · 2021: 46 · 2020: 73 · 2019: 26 · 2018: 26 · 2017: 35 · 2016: 28 · 2015: 29 · 2014: 38 · 2013: 30 · 2012: 28
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns046355-03)
- U.S. Public Health Service (R01-026252)
- National Institute on Aging (P01-AG15343)
- National Institute of Neurological Disorders and Stroke (R01-NS046355, R01-NS46355)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tauopathy, transgenic mouse model, neurofibrillary tangles, tau hyperphosphorylation, tau filaments, frontotemporal dementia
- MeSH terms
- Aging, Animals, Cell Count, Disease Models, Animal, Humans, Memory Disorders, Mice, Transgenic, Nerve Degeneration, Neurofibrillary Tangles, 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 ›
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