Cited by 518Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index; none of the 34 sources its claims cite is checked for support yet.

Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy

Open access

Abstract

Antisense oligonucleotides that reduce tau prevent neuronal loss and reverse tau deposition and seeding in a mouse model of tauopathy.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In PS19 tauopathy mice, antisense oligonucleotide–mediated reduction of human tau prevented and reversed tau pathology, prevented hippocampal and neuronal loss, reduced tau seeding, improved nesting, and extended survival. In non-human primates, tau ASOs distributed throughout the CNS and lowered tau mRNA and protein, supporting investigation of tau-lowering therapy in human tauopathies.

Key findings

  • TauASO-12 reduced human tau mRNA at 4, 8, and 12 weeks after pump implantation (two-way ANOVA p<0.0001; post-hoc 4wk p=0.0250, 8wk p=0.0448, 12wk p<0.0001) without significantly altering murine tau mRNA.
  • In aged 9-month PS19 mice, TauASO-12 reduced sarkosyl-insoluble tau (p=0.006), high-molecular-weight tau oligomers (p=0.004), and phospho-tau (p=0.0104); AT8 pathology was lower than in 9-month starting mice (hippocampus p=0.028, whole brain p=0.011), and Thioflavin S pathology was reversed.
  • Tau reduction prevented hippocampal volume loss (p=0.009), entorhinal cortex area loss (p<0.0001), and CA1 neuronal loss (DAPI/NeuN dual-positive cells p=0.005; cell size p<0.0001), and reversed tau seeding activity (9–12 month TauASO-12 vs starting 9 months p=0.044).
  • TauASO-12 extended median survival from 312 to 348 days (Mantel-Cox p=0.0052) and improved nesting (nest score p=0.040; untorn nestlet weight p=0.014); in Cynomolgus monkeys, intrathecal ASO reduced tau mRNA/protein in brain, spinal cord, and CSF, with CSF tau correlating with hippocampal tau (p=0.01, R²=0.68).

Methods

  • PS19 mice expressing mutant P301S human tau were treated with TauASO-12 or scrambled ASO via intracerebroventricular osmotic pumps at 30 μg/day for 28 days, in 6–9 month and 9–12 month cohorts, with non-transgenic littermate controls.
  • Outcomes included qRT-PCR for human/murine tau mRNA, tau ELISA, sarkosyl-insoluble tau, SDD-AGE, AT8/Thioflavin S/GFAP/NeuN immunofluorescence, hippocampal volume and entorhinal cortex area, FRET flow cytometry tau seeding in HEK-293 cells, survival, and nestlet behavior.
  • Cynomolgus monkeys received intrathecal lumbar bolus tau ASO at 10, 30, or 50 mg; brain, spinal cord, and CSF tau mRNA/protein were measured at 2, 5, or 6 weeks after initial dosing.

Limitations

  • The paper states the study was restricted to the PS19 mouse model, which uses a mutated tau transgene expressed at high levels; effects may partly reflect artificially high mutant tau expression, an important caveat for AD patients without tau mutation or overexpression.
  • The paper states that correlating mouse behavioral changes with human cognitive deficits is challenging, and it remains unclear how the observed benefits will translate to humans; the ASOs also need formal toxicology testing before human trials.
  • Evident from the text: this is preclinical work with no human efficacy data, and some non-human primate groups were small (n=3–4 per treatment), limiting safety and dose-response conclusions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.aag0481

Cites

70 of 70 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

Show all 29 claims

  • It may state two separate claims as one. 22
  • Probably not a substantial claim. 23
39 of 39
  • The paper relies on this without support.

    Tau mutations cause widespread neurodegeneration in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).

    “genetic evidence that tau mutations cause widespread neurodegeneration in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) strongly support the development of therapies targeting tau.”
  • The paper relies on this without support.

    Tau pathology first deposits at 5–6 months of age in PS19 mice.

    “Tau pathology first deposits at 5–6 months of age in PS19 mice.”
  • The paper relies on this without support.

    By the time most patients with tauopathy come to the clinic with symptoms, tau inclusions most likely have already begun to be deposited.

    “By the time most patients with tauopathy come to the clinic with symptoms, tau inclusions most likely have already begun to be deposited.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ANOVA degrees of freedom conflict with the reported sample sizes

    Minor

    The six duration-of-action groups contain 42 mice in total. A two-way ANOVA of these groups cannot have 43 residual degrees of freedom; with six groups, it would have 36.

  • Primate ASO sequence is shorter than the stated modification layout

    Minor

    The stated layout requires 20 nucleotides: five at each terminus and ten in the center. The listed non-human-primate ASO sequence contains 18 nucleotides.

2 of 2

Citations

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Metadata

Authors
DeVos, S. L., Miller, R. L., Schoch, K. M., Holmes, B. B., Kebodeaux, C. S., Wegener, A. J., Chen, G., Shen, T., Tran, H., Nichols, B., Zanardi, T. A., Kordasiewicz, H. B., Swayze, E. E., Bennett, C. F., Diamond, M. I., & Miller, T. M.
Affiliations
  • Washington University in St. Louis (US)
  • Ionis Pharmaceuticals (United States) (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
  • Miller, Rebecca L.
  • Schoch, Kathleen M.
  • Miller, Timothy M.
Venue
Science Translational Medicine
Published
2017-01-25
Volume
9
Issue
374
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
OpenAlex
W2582711285
Cited by
516
References
70
Citations by year
2026: 51 · 2025: 70 · 2024: 59 · 2023: 54 · 2022: 59 · 2021: 58 · 2020: 57 · 2019: 45 · 2018: 44 · 2017: 19
FWCI
33.36
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Tau Consortium
  • NIH (P50 AG05681)
  • National Institute of Neurological Disorders and Stroke (R01NS078398)
  • National Institute on Aging (R21AG044719-01)
  • CurePSP
  • NINDS (K08NS074194)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tauopathy, antisense oligonucleotides, P301S tau, hyperphosphorylated tau, tau inclusions, neuronal loss, hippocampal atrophy, Alzheimer's disease, non-human primates
MeSH terms
Alzheimer Disease, Animals, Brain, Cell Survival, Disease Models, Animal, Hippocampus, Humans, Macaca fascicularis, Mice, Transgenic, Neurons, Phosphorylation, Oligonucleotides, Antisense, tau Proteins, Tauopathies, Mice

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