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

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

Open access
DeVos, Sarah L., Miller, Rebecca L., Schoch, Kathleen M., Holmes, Brandon B., Kebodeaux, Carey S., Wegener, Amy J., Chen, Guo, Shen, Tao +8 more·2017·Science Translational Medicine
DOI 10.1126/scitranslmed.aag0481PMC PMC5792300
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Abstract

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

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.

Claims the paper makes

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

  • Findingown data

    TauASO-12 significantly reduced total human tau mRNA at 4, 8, and 12 weeks post-pump implantation in PS19 mice.

    “Total human tau mRNA was significantly reduced at 4, 8, and 12 weeks post-pump implantation in TauASO-12 treated mice (Fig. 1A) (two-way ANOVA F1,43=22.96, p<0.0001, Bonferroni post-hoc: 4wk p=0.0250, 8wk p=0.0448, 12wk p<0.0001).”
    Quote in the paperSubstantial claim
  • Findingown data

    TauASO-12 treatment prevented further neuronal loss as measured by NeuN positive cell counts in the hippocampus of aged PS19 mice.

    “We confirmed prevention of further neuronal loss as measured by NeuN positive cell counts in the hippocampus following treatment with TauASO-12 in aged PS19 mice (DAPI and NeuN dual positive cells: p=0.005 one-way ANOVA, Sidak post-hoc; cell size: p<0.0001 one-way ANOVA, Sidak post-hoc).”
    Quote in the paperSubstantial claim
  • Findingown data

    GFAP staining was substantially reduced in TauASO-12 treated PS19 mice compared to 12 month old untreated PS19 mice.

    “In PS19 mice treated with TauASO-12, GFAP staining was substantially reduced as compared to 12 month old untreated PS19 mice (Fig. S6A–C).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In 9-12 month old TauASO-12 treated PS19 mice, further hippocampal volume and entorhinal cortex area loss was prevented compared to 9-12 month old PS19 mice treated with Scrambled ASO.

    “In 9–12 month old TauASO-12 treated PS19 mice, further hippocampal volume and entorhinal cortex area loss was prevented when compared to 9–12 month old PS19 mice treated with Scrambled ASO (hippocampus: p=0.009 one-way ANOVA, Sidak post-hoc; entorhinal cortex: p<0.0001 one-way ANOVA, Sidak post-hoc) (Fig. 3A, C; Fig. S7).”
    Quote in the paperSubstantial claim
  • Findingown data

    Tau seeding activity was reversed in the 9-12 month old PS19 cohort treated with TauASO-12 compared to the starting age of 9 months.

    “Additionally, when compared to the starting age of 9 months, tau seeding activity was reversed in the 9–12 month old PS19 cohort treated with TauASO-12 (p=0.044 one-way ANOVA, Sidak post-hoc) (Fig. 4H).”
    Quote in the paperSubstantial claim
  • May combine two claims. 22
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    Following reduction of human tau in the PS19 mouse model of tauopathy, fewer tau inclusions developed and pre-existing phosphorylated tau and thioflavin S pathology was reversed.

    “Following reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed and pre-existing phosphorylated tau and thioflavin S pathology was reversed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TauASO-12 treated PS19 mice performed significantly better on the nestlet task, making better nests and leaving less untorn nestlet weight.

    “Mice treated with TauASO-12 performed significantly better on the nestlet task, both making better nests (p=0.040 Kruskal-Wallis, Dunn’s post-hoc) and leaving less untorn nestlet weight behind (p=0.014 one-way ANOVA, Sidak post-hoc) (Fig. 5B, C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mouse survival was extended and pathological tau seeding was reversed by tau reduction.

    “In addition, mouse survival was extended and pathological tau seeding was reversed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In aged 9-month-old PS19 mice, TauASO-12 treatment significantly reduced human tau mRNA and total human tau protein.

    “In this older cohort, human tau mRNA (p=0.0003, one-way ANOVA, Sidak post-hoc; Fig. S3B) as well as total human tau protein was significantly reduced after TauASO-12 treatment (p=0.024, one-way ANOVA, Sidak post-hoc; Fig. 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no difference in human or murine tau mRNA between saline and scrambled ASO control treatments.

    “There was no difference in either human tau (two-tailed student t-test, p=0.703) or murine tau (two-tailed student t-test, p=0.496) mRNA between saline and scrambled ASO control treatments, and thus these values were combined as single control values.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TauASO-12 diffused throughout the mouse brain and visibly persisted to the end of the 12-week treatment period.

    “TauASO-12 diffused throughout the mouse brain and visibly persisted to the end of the 12-week treatment period (Fig. 1C; Fig. S2) (15, 18).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In non-human primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid.

    “In non-human primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 6-month-old PS19 mice treated with TauASO-12, human tau mRNA and human tau protein were significantly reduced compared to scrambled control.

    “Human tau mRNA (one-way ANOVA, Sidak post-hoc p=0.004; Fig. S3A) and human tau protein (one-way ANOVA, Sidak post-hoc p=0.011; Fig. 1D) was significantly reduced in the TauASO-12 group compared to the scrambled control group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The resolution of tau pathology was accompanied by prevention of hippocampal volume loss, neuronal death, and nesting deficits.

    “The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TauASO-12 treatment reduced total high molecular weight tau oligomers and PHF-1 positive phospho-tau in aged PS19 mice.

    “There was a reduction in total HMW tau oligomers (p=0.004, two-tailed t-test) and phospho-tau (p=0.0104, two-tailed t-test) in the TauASO-12 treated mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Despite there being more tau aggregates in the 9-12 month old treated PS19 cohort compared to the 6-9 month old animals, seeding activity was reduced equally in both groups.

    “Interestingly, despite there being more tau aggregates in the 9–12 month old treated PS19 cohort compared to the 6–9 month old animals, seeding activity was reduced equally in both groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    At two weeks after ASO treatment in non-human primates, tau mRNA was effectively decreased and tau protein was also decreased, though not to the same degree.

    “At two weeks after ASO treatment, tau mRNA was effectively decreased (Fig. 6D). Protein was also decreased, though not to the same degree, likely due to the long half-life of tau (35) (Fig. 6E).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Yamada K Holth JK Liao F Stewart FR Mahan TE Jiang H Cirrito JR Patel TK Hochgräfe K Mandelkow EM Holtzman DM Neuronal activity regulates extracellular tau in vivo J Exp Med 211 387 93 2014 24534188 PMC3949564

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The longer six week duration showed continued tau mRNA reduction as well as improved tau protein reduction compared to the two week duration in non-human primates.

    “The longer six week duration showed both continued tau mRNA reduction as well as improved tau protein reduction compared to the two week duration (Fig. 6D, E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In mice, genetic ablation of endogenous tau is well tolerated, with a minor motor phenotype developing only after 12-16 months.

    “In mice, genetic ablation of endogenous tau is well tolerated with a minor motor phenotype developing only after 12–16 months (12–14).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Lei P Ayton S Finkelstein DI Spoerri L Ciccotosto GD Wright DK Wong BXW Adlard PA Cherny RA Lam LQ Roberts BR Volitakis I Egan GF McLean CA Cappai R Duce JA Bush AI Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export Nat Med 18 291 5 2012 22286308 source

      Not checked in the free run.

    • cites [13] Morris M Hamto P Adame A Devidze N Masliah E Mucke L Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice Neurobiol Aging 34 1523 9 2013 23332171 PMC3596503

      Not checked in the free run.

    • cites [14] Li Z Hall AM Kelinske M Roberson ED Seizure resistance without parkinsonism in aged mice after tau reduction Neurobiol Aging 35 2617 24 2014 24908165 PMC4171213

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of SOD1-related ALS, mouse models of Huntington's disease and FTDP-17, and in C9ORF72 patient-derived cell lines.

    “Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of superoxide dismutase 1 (SOD1)-related ALS (17), mouse models of Huntington’s disease (18) and FTDP-17 (19), and in C9ORF72 patient-derived cell lines (20, 21).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Smith RA Miller TM Yamanaka K Monia BP Condon TP Hung G Lobsiger CS Ward CM McAlonis-Downes M Wei H Wancewicz EV Bennett CF Cleveland DW Antisense oligonucleotide therapy for neurodegenerative disease J Clin Invest 116 2290 6 2006 16878173 PMC1518790 source

      Not checked in the free run.

    • cites [18] Kordasiewicz HB Stanek LM Wancewicz EV Mazur C McAlonis MM Pytel KA Artates JW Weiss A Cheng SH Shihabuddin LS Hung G Bennett CF Cleveland DW Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis Neuron 74 1031 44 2012 22726834 PMC3383626 source

      Not checked in the free run.

    • cites [19] Schoch KM DeVos SL Miller RL Chun SJ Norrbom M Wozniak DF Dawson HN Bennett CF Rigo F Miller TM Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model Neuron 90 941 7 2016 27210553 PMC5040069 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Administering SOD1 ASOs into the CNS of human ALS patients via the CSF has been well tolerated.

    “Administering SOD1 ASOs into the CNS of human ALS patients via the CSF has been well tolerated (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Miller TM Pestronk A David W Rothstein J Simpson E Appel SH Andres PL Mahoney K Allred P Alexander K Ostrow LW Schoenfeld D Macklin EA Norris DA Manousakis G Crisp M Smith R Bennett CF Bishop KM Cudkowicz ME An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study Lancet Neurol 12 435 42 2013 23541756 PMC3712285 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice that completely lack tau have proven to be phenotypically normal in learning/memory and general cognition, with a minor motor phenotype developing later in life.

    “Surprisingly, mice that completely lack tau have proven to be phenotypically normal in terms of learning/memory and general cognition (13, 14, 50) with a minor motor phenotype developing later in life, the severity of which varies (12–14, 56).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [13] Morris M Hamto P Adame A Devidze N Masliah E Mucke L Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice Neurobiol Aging 34 1523 9 2013 23332171 PMC3596503

      Not checked in the free run.

    • cites [14] Li Z Hall AM Kelinske M Roberson ED Seizure resistance without parkinsonism in aged mice after tau reduction Neurobiol Aging 35 2617 24 2014 24908165 PMC4171213

      Not checked in the free run.

    • cites [50] Roberson ED Scearce-Levie K Palop JJ Yan F Cheng IH Wu T Gerstein H Yu GQ Mucke L Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model Science 316 750 4 2007 17478722 source

      Not checked in the free run.

    • cites [12] Lei P Ayton S Finkelstein DI Spoerri L Ciccotosto GD Wright DK Wong BXW Adlard PA Cherny RA Lam LQ Roberts BR Volitakis I Egan GF McLean CA Cappai R Duce JA Bush AI Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export Nat Med 18 291 5 2012 22286308 source

      Not checked in the free run.

    • cites [56] van Hummel A Bi M Ippati S van der Hoven J Volkerling A Lee WS Tan DCS Bongers A Ittner A Ke YD Ittner LM No Overt Deficits in Aged Tau-Deficient C57Bl/6.Mapttm1(EGFP)Kit GFP Knockin Mice PLoS One 11 e0163236 2016 27736877 PMC5063411

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Each age group was processed together and all brains across both age groups were stained and imaged at the same time.

    “Each age group – 6–9 month old and 9–12 month old – was processed together and all brains across both age groups were stained and imaged at the same time.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The middle empty lane was used to subtract background from all samples in the SDD-AGE analysis.

    “The middle empty lane was used to subtract background from all samples.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Experiments involving animals were approved by the Animal Studies Committee at Washington University in St. Louis.

    “Experiments involving animals were approved by the Animal Studies Committee at Washington University in St. Louis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All images were taken with the same fluorescent settings.

    “All images were taken with the same fluorescent settings and subsequently adjusted equally for brightness and contrast to ensure accurate pathology quantification.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Correlating behavioral changes in mice with cognitive deficits in humans is challenging and it remains unclear how the benefits observed here will translate to humans.

    “Additionally, correlating behavioral changes in mice with cognitive deficits in humans is challenging and it remains unclear how the benefits we observed here will translate to humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Each sample in the tau seeding assay was analyzed in triplicate.

    “Each experiment was performed using 20,000 cells per replicate and each sample was analyzed in triplicate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All pathology quantification was carried out blinded.

    “All pathology quantification was carried out blinded.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All images were subsequently adjusted equally for brightness and contrast to ensure accurate pathology quantification.

    “All images were taken with the same fluorescent settings and subsequently adjusted equally for brightness and contrast to ensure accurate pathology quantification.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Staining for all sections analyzed was carried out on the same day.

    “Staining for all sections analyzed were carried out on the same day and imaged together to reduce staining batch variability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    All sections were imaged together to reduce staining batch variability.

    “Staining for all sections analyzed were carried out on the same day and imaged together to reduce staining batch variability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A pilot cohort of n=5 per treatment was sufficient to see significant differences in tau expression and pathology.

    “To determine sample size for tau reduction and pathology, a pilot cohort of n=5/treatment was analyzed and found to be sufficient to see significant differences in tau expression and pathology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal protocols were approved by the Washington University in St. Louis Institutional Animal Care and Use Committee.

    “All animal protocols were approved by the Washington University in St. Louis Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Mice were litter-matched, age-matched, and gender matched to keep treatment groups as similar as possible.

    “For all studies, mice were litter-matched, age-matched, and gender matched to keep the treatment groups as similar as possible.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Dominantly inherited forms of neurodegenerative diseases caused by mutations in tau, SOD1, huntingtin or other proteins are all highly age-dependent, suggesting mechanisms early in life may adequately mitigate the effects of these disease-causing mutant proteins and delay disease onset.

    “Dominantly inherited forms of neurodegenerative diseases caused by mutations in tau, SOD1, huntingtin or other proteins are all highly age-dependent, suggesting mechanisms early in life may adequately mitigate the effects of these disease-causing mutant proteins and delay disease onset.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    In AD, tau burden appears to directly correlate with disease progression and cognitive decline.

    “In AD, tau burden appears to directly correlate with disease progression and cognitive decline (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Nelson PT Alafuzoff I Bigio EH Bouras C Braak H Cairns NJ Castellani RJ Crain BJ Davies P Del Tredici K Duyckaerts C Frosch MP Haroutunian V Hof PR Hulette CM Hyman BT Iwatsubo T Jellinger KA Jicha GA Kövari E Kukull WA Leverenz JB Love S Mackenzie IR Mann DM Masliah E McKee AC Montine TJ Morris JC Schneider JA Sonnen JA Thal DR Trojanowski JQ Troncoso JC Wisniewski T Woltjer RL Beach TG Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature J Neuropathol Exp Neurol 71 362 81 2012 22487856 PMC3560290 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sample sizes were chosen based on previous experience with tau ASOs in the lab and therapeutic studies carried out by others using the same PS19 mouse line.

    “Sample sizes were chosen based both on previous experience with tau ASOs in the lab as well as therapeutic studies carried out by others using the same PS19 mouse line.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Nest quality was scored by a blinded observer.

    “The untorn nestlets were weighed and nests scored by a blinded observer.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The tau seeding analyses, quantification of AT8 staining, hippocampal and entorhinal volume, NeuN/DAPI counts, cell size analysis, survival, and nestlet behavior were all carried out blinded.

    “The tau seeding analyses, quantification of AT8 staining, hippocampal and entorhinal volume, NeuN/DAPI counts, cell size analysis, survival, and nestlet behavior were all carried out blinded.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All hippocampal volume and entorhinal cortex analyses were carried out blinded.

    “All hippocampal volume and entorhinal cortex analyses were carried out blinded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In approximately 40% of Frontotemporal Dementia (FTD) cases, tau is the primary pathology.

    “Further, in approximately 40% of Frontotemporal Dementia (FTD) cases, tau is the primary pathology (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Goedert M Ghetti B Spillantini MG Frontotemporal dementia: implications for understanding Alzheimer disease Cold Spring Harb Perspect Med 2 a006254 2012 22355793 PMC3281593

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The reversal of tau pathology by ASO-mediated reduction of human tau in PS19 mice is consistent with previous studies using a regulated transgene and shows therapeutic potential for tau-targeted strategies by demonstrating reduction in tau seeding activity and rescue of neuronal loss in a clinically-relevant tauopathy mouse model.

    “The reversal of tau pathology by ASO-mediated reduction of human tau in PS19 mice is not only consistent with previous studies using a regulated transgene, but also shows the therapeutic potential for tau-targeted strategies by demonstrating reduction in tau seeding activity and rescue of neuronal loss in a clinically-relevant tauopathy mouse model.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Polydoro M de Calignon A Suárez-Calvet M Sanchez L Kay KR Nicholls SB Roe AD Pitstick R Carlson GA Gómez-Isla T Spires-Jones TL Hyman BT Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer’s disease J Neurosci 33 13300 11 2013 23946388 PMC3742920

      Not checked in the free run.

    • cites [38] Santacruz K Lewis J Spires T Paulson J Kotilinek L Ingelsson M Guimaraes A DeTure M Ramsden M McGowan E Forster C Yue M Orne J Janus C Mariash A Kuskowski M Hyman B Hutton M Ashe KH Tau suppression in a neurodegenerative mouse model improves memory function Science 309 476 81 2005 16020737 PMC1574647

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Previous reports show that on SDD-AGE, low-molecular-weight tau accumulates at the bottom of the gel and high-molecular-weight tau oligomers appear as smears at the top.

    “Previous reports of HMW and LMW tau run on SDD-AGE show an accumulation of LMW tau at the bottom of the gel with smears of HMW tau oligomers at the top (7, 63–65).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Yanamandra K Kfoury N Jiang H Mahan TE Ma S Maloney SE Wozniak DF Diamond MI Holtzman DM Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo Neuron 80 402 14 2013 24075978 PMC3924573 source

      Not checked in the free run.

    • cites [63] Sanders DW Kaufman SK DeVos SL Sharma AM Mirbaha H Li A Barker SJ Foley AC Thorpe JR Serpell LC Miller TM Grinberg LT Seeley WW Diamond MI Distinct tau prion strains propagate in cells and mice and define different tauopathies Neuron 82 1271 88 2014 24857020 PMC4171396 source

      Not checked in the free run.

    • cites [64] Takeda S Wegmann S Cho H DeVos SL Commins C Roe AD Nicholls SB Carlson GA Pitstick R Nobuhara CK Costantino I Frosch MP Müller DJ Irimia D Hyman BT Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain Nat Commun 6 8490 2015 26458742 PMC4608380 source

      Not checked in the free run.

    • cites [65] Takeda S Commins C DeVos SL Nobuhara CK Wegmann S Roe AD Costantino I Fan Z Nicholls SB Sherman AE Trisini Lipsanopoulos AT Scherzer CR Carlson GA Pitstick R Peskind ER Raskind MA Li G Montine TJ Frosch MP Hyman BT Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer’s disease mouse model and human patients Ann Neurol 2016 10.1002/ana.24716 PMC5016222 27351289 source

      Not checked in the free run.

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?

  • Tau ablation confers neuronal protection resulting in the recovery of behavioral deficits in neurodegenerative and neurodevelopmental models.

    “Numerous studies across neurodegenerative and neurodevelopmental models have shown that tau ablation confers neuronal protection resulting in the recovery of behavioral deficits [56, 75, 76, 121–123].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [121]

    The Discussion (page unavailable) reports that tau knockdown in PS19 tauopathy mice halted neuronal loss and protected against nesting-behavior deficits. The Results also report improved nesting after treatment. This supports the claim for a neurodegenerative mouse model, but the intervention was tau reduction, not ablation, and this paper does not establish the claimed effect in neurodevelopmental models. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ASO-mediated tau reduction has shown promising results in the treatment of Alzheimer's disease after local injection of Tau-ASO using an intracerebroventricular pump.

    “because ASO-mediated tau reduction has shown promising results in the treatment of Alzheimer’s disease after the local injection of the Tau-ASO using an intracerebroventricular (ICV) pump (31, 32).”

    From Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection (2020) · cites this paper as [32]

    The Results (‘Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice’ and ‘Tau ASO Treatment Prevents AT8-positive Tau Deposition’; page unavailable) report tau reduction and reduced pathology in PS19 mice. The Methods (‘Surgical Placement of Intracerebroventricular (ICV) Pumps and Tissue Collection’; page unavailable) confirm delivery by ICV pump. The Discussion calls this preclinical work a basis for a possible Alzheimer’s disease therapy; it does not report treatment results in people with Alzheimer’s disease. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Preclinical studies in tau-overexpressing mice suggest that anti-tau ASO may be viable in tauopathies.

    “Preclinical studies using tau-overexpressing mice suggest this approach may be viable in tauopathies (DeVos et al., 2017).”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as DeVos et al., 2017

  • Anti-sense oligonucleotides to decrease tau expression lead to reversal of tau pathology in mouse and non-human primate models.

    “An alternative and promising strategy has focused on using anti-sense oligonucleotides (ASO) to decrease tau expression, leading to reversal of tau pathology in mouse and non-human primate models”

    From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as DeVos et al., 2017

  • In preclinical models, decreasing tau protein levels via ASO strategies and recently by engineered zinc-finger transcription factors was shown to be durable and to reverse tau pathology.

    “In fact, in preclinical models, decreasing tau protein levels via ASO strategies185,186 and recently by engineered zinc-finger transcription factors187 was shown to be durable and to reverse tau pathology.”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [185]

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

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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.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2017-01-25
Volume
9
Issue
374
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.aag0481
PMC
PMC5792300
OpenAlex
W2582711285
Semantic Scholar
e8bc8636bc48a82df873910876a5024209412f6a
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
Licence
www.sciencemag.org/about/science-licenses-journal-article-reuse (vor, 365 d)
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
  • 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
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

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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