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Cited by 44Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingAmyotrophic Lateral Sclerosis Research

Kinetics of human mutant tau prion formation in the brains of 2 transgenic mouse lines

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Woerman, Amanda L., Patel, Smita, Kazmi, Sabeen A., Oehler, Abby, Freyman, Yevgeniy, Espiritu, Lloyd, Cotter, Robert, Castaneda, Julian A. +2 more·2017·JAMA Neurology
DOI 10.1001/jamaneurol.2017.2822PMC PMC5822201
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Abstract

Importance: Accumulation of the protein tau is a defining characteristic of several neurodegenerative diseases. Thorough assessment of transgenic (Tg) mouse lines that replicate this process is critical for establishing the models used for testing anti-tau therapeutics in vivo. Objective: To define a consistent mouse model of disease for use in future compound efficacy studies. Design, Setting, and Participants: In this time course study, cohorts of Tg and control mice were euthanized at defined intervals. Collected brains were bisected down the midline. One half was frozen and used to measure the tau prion content, while the other half was fixed for immunostaining with anti-tau antibodies. All mice were maintained at the Hunters Point Animal Facility at the University of California, San Francisco, and all experiments were performed at the Mission Bay Campus of the University of California, San Francisco. Study animals were PS19, homozygous and hemizygous Tg(MAPT*P301S), and B6/J mice. The study dates were August 9, 2010, to October 3, 2016. Main Outcomes and Measures: Tau prions were measured using a cell-based assay. Neuropathology was measured by determining the percentage area positive for immunostaining in defined brain regions. A separate cohort of mice was aged until each mouse developed neurological signs as determined by trained animal technicians to assess mortality. Results: A total of 1035 mice were used in this time course study. These included PS19 mice (51.2% [126 of 246] male and 48.8% [120 of 246] female), Tg(MAPT*P301S+/+) mice (52.3% [216 of 413] male, 43.8% [181 of 413] female, and 3.9% [16 of 413] undetermined), Tg(MAPT*P301S+/-) mice (51.8% [101 of 195] male and 48.2% [94 of 195] female), and B6/J mice (49.7% [90 of 181] male and 50.3% [91 of 181] female). While considerable interanimal variability in neuropathology, disease onset, and tau prion formation in the PS19 mice was observed, all 3 measures of disease were more uniform in the Tg(MAPT*P301S+/+) mice. Comparing tau prion formation in Tg(MAPT*P301S+/+) mice with B6/J controls, the 95% CIs for the 2 mouse lines diverged before age 5 weeks, and significant (P < .05) neuropathology in the hindbrain of 24-week-old mice was quantifiable. Conclusions and Relevance: The assessment of disease progression using 3 criteria showed that disease onset in PS19 mice is too variable to obtain reliable measurements for drug discovery research. However, the reproducibility of tau prion formation in young Tg(MAPT*P301S+/+) mice establishes a rapid assay for compound efficacy in vivo.

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  • The variability observed in p-tau burden across the lifespan is consistent with earlier reports showing significant variability in spontaneous hippocampal p-tau accumulation in aged male and female PS19 mice.

    “The variability which we observed in p-tau burden across the lifespan is consistent with earlier reports showing significant variability in spontaneous hippocampal p-tau accumulation in aged male and female PS19 mice (Sun et al., 2020; Woerman et al., 2017).”

    From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Woerman et al., 2017

    The Discussion (page not provided) reports substantial interanimal variability in AT8 staining in 31-week-old PS19 mice and in tau-prion content at 22–38 weeks. The study included males and females, but the cited passages do not establish variability specifically in spontaneous hippocampal p-tau accumulation in each sex; its tau-prion assay used half-brains rather than isolated hippocampi. (LLM, conf=0.88)

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  • The pattern of resistance is consistent with a report of widely variable ages of induction of tau pathology in the PS19 model.

    “This pattern is also consistent with a report of widely variable ages of induction of tau pathology in the PS19 model (Woerman et al., 2017).”

    From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Woerman et al., 2017

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Authors
Woerman, A. L., Patel, S., Kazmi, S. A., Oehler, A., Freyman, Y., Espiritu, L., Cotter, R., Castaneda, J. A., Olson, S. H., & Prusiner, S. B.
Affiliations
University of California, San Francisco (US)
Corresponding author
Prusiner, Stanley B.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2017-12-01
Volume
74
Issue
12
Pages
1464
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2017.2822
PMC
PMC5822201
OpenAlex
W2766659688
Cited by
44
References
65
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 10 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 3
FWCI
2.43
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • University of California, San Francisco
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
tauopathy, transgenic mouse model, PS19 mice, neuropathology, disease onset, Alzheimer's disease, interindividual variability
MeSH terms
Animals, Brain, Disease Models, Animal, Female, Homozygote, Humans, Kinetics, Male, Mice, Transgenic, Mutation, Prions, Reproducibility of Results, tau Proteins, Tauopathies, Mice, Hemizygote

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