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Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy
Open accessAbstract
Antisense oligonucleotides that reduce tau prevent neuronal loss and reverse tau deposition and seeding in a mouse model of tauopathy.
Overview
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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.
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30 Own result · 16 Not checked yet · 16 Own method · 5 Own interpretation · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Hippocampal Volume and Neuronal Loss are Prevented After Human Tau Reduction
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In the paper
“In PS19 mice treated with TauASO-12, GFAP staining was substantially reduced as compared to 12 month old untreated PS19 mice (Fig. S6A–C).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Reverses Tau Inclusions in Aged PS19 Mice
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Hippocampal Volume and Neuronal Loss are Prevented After Human Tau Reduction
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Reducing Human Tau Prevents and Reverses Tau Seeding Capability
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In the paper
“9–12 month old PS19 mice treated with TauASO-12 showed substantially less AT8 staining in the hippocampus and the whole brain compared to both age-matched 12 month old PS19 mice treated with scrambled ASO and untreated mice (one-way ANOVA, Sidak post-hoc: hippocampus p<0.0001, whole brain p<0.0001), as well as the 9 month old PS19 mice starting group (one-way ANOVA, Sidak post-hoc: hippocampus p=0”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Reverses Tau Inclusions in Aged PS19 Mice
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In the paper
“When stained for neurofibrillary tangles using Thioflavin S, a similar pattern emerged with TauASO-12 treated PS19 mice showing a reversal of neurofibrillary tangle pathology (one-way ANOVA, Sidak post-hoc: 9–12 PS19 ASO-12 vs 6–9 PS19 Scrambled ASO p=0.0486; 9–12 PS19 ASO-12 vs 9–12 PS19 Scrambled ASO p=0.0078) (Fig. 2Q; quantification, Fig. S5).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Reverses Tau Inclusions in Aged PS19 Mice
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In the paper
“TauASO-12 treatment greatly reduced the amount of AT8 tau pathology deposition in the hippocampus (one-way ANOVA, Sidak post-hoc p=0.0003) (Fig. 1E, I) and in whole brain sections (one-way ANOVA, Sidak post-hoc p=0.008) (Fig. 1F, J).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Prevents AT8-positive Tau Deposition
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In the paper
“Murine tau mRNA was not significantly altered (Fig. 1B) (two-way ANOVA F1,43=1.27, p=0.267, Bonferroni post-hoc: 4wk p=0.265, 8wk p>0.999, 12wk p>0.999).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice
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In the paper
“No significant differences were seen at any of the time points for either human tau (one-way ANOVA, Sidak post-hoc: 4wk p=0.968, 8wk p=0.926, 12wk p=0.331) or murine tau mRNA (one-way ANOVA, Sidak post-hoc: 4wk p=0.948, 8wk p=0.824, 12wk p=0.501) (Fig. S1).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice
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In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Abstract
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Lowering Human Tau Prolongs Mouse Survival and Rescues Nesting Deficits
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“In addition, mouse survival was extended and pathological tau seeding was reversed.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Abstract
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Reverses Tau Inclusions in Aged PS19 Mice
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In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice
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“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > ASOs Are Distributed Throughout the Adult Murine Brain
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In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Abstract
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In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Prevents AT8-positive Tau Deposition
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In the paper
“The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Abstract
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In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASO Treatment Reverses Tau Inclusions in Aged PS19 Mice
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In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
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“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASOs Reduce Tau in a Non-Human Primate
What the sources say
- Not checked yetcites [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
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Tau ASOs Reduce Tau in a Non-Human Primate
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In the paper
“In mice, genetic ablation of endogenous tau is well tolerated with a minor motor phenotype developing only after 12–16 months (12–14).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Administering SOD1 ASOs into the CNS of human ALS patients via the CSF has been well tolerated (22).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Introduction
What the sources say
- Not checked yetcites [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
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In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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
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“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Study Design
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“The middle empty lane was used to subtract background from all samples.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Semi-Denaturing Detergent Agarose Gel Electrophoresis (SDD-AGE)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments involving animals were approved by the Animal Studies Committee at Washington University in St. Louis.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Animals
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All images were taken with the same fluorescent settings and subsequently adjusted equally for brightness and contrast to ensure accurate pathology quantification.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Immunofluorescence
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each experiment was performed using 20,000 cells per replicate and each sample was analyzed in triplicate.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Tau Seeding Assay
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All pathology quantification was carried out blinded.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Tau Pathology Quantification
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All images were taken with the same fluorescent settings and subsequently adjusted equally for brightness and contrast to ensure accurate pathology quantification.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Immunofluorescence
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Staining for all sections analyzed were carried out on the same day and imaged together to reduce staining batch variability.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Thioflavin S Staining
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Staining for all sections analyzed were carried out on the same day and imaged together to reduce staining batch variability.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Thioflavin S Staining
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Statistics
plainn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal protocols were approved by the Washington University in St. Louis Institutional Animal Care and Use Committee.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Surgical Placement of Intracerebroventricular (ICV) Pumps and Tissue Collection
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For all studies, mice were litter-matched, age-matched, and gender matched to keep the treatment groups as similar as possible.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Study Design
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“In AD, tau burden appears to directly correlate with disease progression and cognitive decline (3).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Study Design
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The untorn nestlets were weighed and nests scored by a blinded observer.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Nestlet Behavior
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Study Design
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All hippocampal volume and entorhinal cortex analyses were carried out blinded.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Hippocampal Volume and Entorhinal Cortex Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Further, in approximately 40% of Frontotemporal Dementia (FTD) cases, tau is the primary pathology (43).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
What the sources say
- Not checked yetcites [43] Goedert M Ghetti B Spillantini MG Frontotemporal dementia: implications for understanding Alzheimer disease Cold Spring Harb Perspect Med 2 a006254 2012 22355793 PMC3281593
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Semi-Denaturing Detergent Agarose Gel Electrophoresis (SDD-AGE)
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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 the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice
“control [saline vehicle or 30μg/day (total 840μg) scrambled ASO] treatment (4wk n=10; 8wk n=5; 12wk n=8) or 30μg/day (total 840μg) TauASO-12 human tau reduction treatment (4wk n=3; 8wk n=5; 12wk n=11) for 28 days.”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Results > Human Tau Antisense Oligonucleotides Reduce Human Tau mRNA in mice
“two-way ANOVA F1,43=22.96”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Antisense Oligonucleotides
“five nucleotides on the 5′- and 3′-termini containing 2′-O-methoxyethyl modifications and 10 unmodified central oligodeoxynucleotides”
§ Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy > Materials and Methods > Antisense Oligonucleotides
“For Non-Human Primate work: Tau ASO sequence – 5′ CCGTTTTCTTACCACCCT 3′.”
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.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2017-01-25
- Volume
- 9
- Issue
- 374
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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