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PreprintCited by 0Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease

Open access
Chimal-Juárez, Enrique, Patel, Henika, Jury-Garfe, Nur, Dabin, Luke C., Vidal, Ruben, Kim, Jungsu, Lasagna-Reeves, Cristian A.·2026·bioRxiv
DOI 10.64898/2026.05.12.724684PMC PMC13192590
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Abstract

Tau is a microtubule-associated protein with diverse roles in the healthy brain but contributes to neurodegenerative disorders when dysregulated. Although tau ablation has shown protective effects in several disease models, how its absence confers this protection remain unclear. Here, we performed and analyzed single-nucleus RNA sequencing on cortices of aged tau knockout ( Mapt ⁻/⁻ ) mice in a wild type background as well as in a vascular amyloid model to evaluate the effect on disease context. Comparisons in a wild type setting revealed that tau ablation induced compensatory remodeling across multiple cell types. Excitatory neurons expanded into a distinct subtype with unique glutamatergic signaling, astrocytes adopted synaptoprotective states, oligodendrocytes upregulated genes supporting connectivity and plasticity, and microglia engaged structural remodeling programs. In contrast, in disease, tau removal not only restored functions disrupted by vascular amyloid pathology, but also generated new phenotypes. Excitatory neurons rewired receptor and postsynaptic signaling, astrocytes and oligodendrocytes recovered wild-type-like gene programs related to neurotransmitter cycling, synaptic support, and myelin integrity, and microglia reprogrammed toward sensing and mounting responses. Together, these findings demonstrate that tau ablation reshapes brain cellular programs in a context-dependent manner, exerting adaptive responses in the otherwise healthy brain while restoring homeostatic functions under vascular amyloid pathology. These results position tau as a key regulator of neuronal-glial network balance and highlight the importance of understanding how tau influences distinct cellular programs within specific disease environments.

AI snapshot

Written from the paper’s full text.

TL;DR

Tau ablation in aged mice rewires cortical cell-type transcriptional programs in a context-dependent manner, producing compensatory remodeling in healthy brain and restoring some disease-disrupted glial programs in a vascular amyloid model. The authors conclude tau regulates neuronal-glial network balance, with tau removal generating disease-independent adaptive programs in neurons and restorative programs in glia.

Key findings

  • In aged WT vs Mapt−/− cortex, tau ablation expanded a distinct excitatory neuron subtype, ExNeuron12, with altered glutamatergic signaling; ExNeuron12 showed higher overlap with human iPSC-derived glutamatergic neurons treated with tau ASO (odds ratio = 2.23, Adj-P = 7.62E-09) than with non-targeting ASO (odds ratio = 1.7, Adj-P = 0.39).
  • Mapt−/− astrocytes showed 757 upregulated and 248 downregulated transcripts, with enrichment in synaptic signaling, axon guidance, and ion transport; Mapt−/− oligodendrocytes showed 220 upregulated and 21 downregulated transcripts, enriched for neuronal communication, plasticity, axonogenesis, and synaptic transmission; Mapt−/− microglia showed 137 Mapt−/−-specific DEGs enriched for synaptic terms.
  • In the Tg-FDD CAA model, tau ablation expanded ExNeuron6, with 20 “Red” genes exclusively upregulated in Tg-FDD;Mapt−/− ExNeuron6, enriched for glutamatergic neurotransmission, NMDA receptor activation, synaptic transmission, and long-term potentiation.
  • In Tg-FDD;Mapt−/− glia, tau removal restored WT-like “Yellow” gene sets: astrocytes recovered neurotransmitter cycling/synaptic support programs, oligodendrocytes recovered phagocytic, neuron projection, and myelination programs, and microglia showed 13 “Red” and 4 “Yellow” genes; CellChat predicted increased communication in Mapt−/− but reduced global communication in Tg-FDD;Mapt−/− with selective synaptic pathway increases.

Methods

  • snRNA-seq was performed on cortex from 22-month-old male WT, Mapt−/−, Tg-FDD, and Tg-FDD;Mapt−/− mice, with n=3 per genotype; nuclei were isolated with Singulator S100 and processed with 10x Chromium.
  • Data were analyzed in Cell Ranger, SoupX, DoubletFinder, Seurat/SCTransform, Enrichr, speckle, CellChat v2, and a three-way differential expression/3D volcano framework; astrocyte subclusters were compared to published programs by cosine similarity.
  • Human iPSC-derived glutamatergic neuron bulk RNA-seq from tau ASO vs non-targeting ASO (GEO GSE204931) was mapped to mouse orthologs and compared with mouse snRNA-seq signatures using Fisher’s exact test.

Limitations

  • The paper does not include a dedicated limitations section.
  • Evident from the text: only male mice were used, n=3 per genotype, and analyses were restricted to cortex from 22-month-old mice, limiting sex, sample-size, age, and brain-region generalization.
  • Evident from the text: Mapt−/− is a global knockout, so glial changes may reflect both cell-autonomous and non-cell-autonomous effects; CellChat findings are inferred from ligand-receptor expression rather than directly validated intercellular signaling.

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

Integrity signals

Registry

Crossref · 10.64898/2026.05.12.724684

Cites

152 of 152 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

80 of 115 cited sources checked · 31 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    The Tg-FDD mouse model accumulates Danish amyloid exclusively in the vasculature.

    “The Tg-FDD mouse model accumulates Danish amyloid exclusively in the vasculature.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [88] source

      The Discussion (page not provided) reports parenchymal ADan deposition, including some amyloid deposits in the cortex and hippocampus. The model therefore does not accumulate Danish amyloid exclusively in the vasculature. (LLM, conf=0.95)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [120] 2019, Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy, Acta Neuropathologica Communications source

      The Results (Fig. 4; page unavailable) confirm ADan amyloid deposits in Tg-FDD cerebral vessels. But the same section reports intracellular ADan oligomers in the cortex, so the paper does not support the word “exclusively.” (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    In a vascular injury model induced by high-salt diet, tau ablation rescued molecular pathways underlying neurovascular dysfunction.

    “In a vascular injury model induced by high-salt diet, tau ablation rescued molecular pathways underlying neurovascular dysfunction [87].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [87] Faraco, G. , et al., Dietary salt promotes cognitive impairment through tau phosphorylation. Nature, 2019. 574(7780): p. 686-690. source

      The tau-null experiment (passage [6]) reports that high-salt-fed mice avoided cognitive impairment but still had an attenuated cerebral blood-flow response, a measure of neurovascular dysfunction. The Abstract (passage [2]) likewise says cognitive impairment was absent despite persistent hypoperfusion and neurovascular dysfunction. Tau ablation therefore rescued cognition, not the neurovascular dysfunction attributed to it in the claim. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Genetic deletion studies indicate that endogenous tau participates in neuronal processes including cytoskeletal regulation, mitochondrial dynamics, synaptic plasticity, network activity, and DNA/RNA stability.

    “Genetic deletion studies indicate that endogenous tau participates in a range of neuronal processes, including cytoskeletal regulation, mitochondrial dynamics, synaptic plasticity, network activity [10–22], and stability of DNA and RNA stability [23].”
    Quote in the paperSubstantial claim4 of 10 sources checked
    • cites [10] source
    • cites [11] 2022, Tau phosphorylation and PAD exposure in regulation of axonal growth, Front Cell Dev Biol

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [12] source
    • cites [13] source
    • cites [14] source
    • cites [15] source

      The citation to this paper is attached to DNA and RNA stability. The Results (§3.1, p. 5) examine calmodulin localization in tau-deficient neurons, and the Discussion (§4, p. 5) addresses calbindin expression; neither addresses DNA or RNA stability. Searches for DNA/RNA stability and genomic integrity found no relevant passage in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [16] source

      The Introduction describes tau’s role in microtubule stabilization, and the Results report altered synaptic properties in tau-knockout granule neurons. The Discussion also mentions synaptic-plasticity changes, while the References list work on tau-dependent mitochondrial pausing and network hyperexcitability. This paper does not itself establish effects on mitochondrial dynamics or network activity. DNA/RNA stability is attached to a different citation, [23], in the citing sentence. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [17] source

      The mitochondrial-movement results (page unavailable) compare wild-type and tau-knockout neurons and report faster anterograde movement and less pausing without tau, supporting the mitochondrial-dynamics part of the claim. The Discussion (page unavailable) also describes a possible structural role for tau in microtubule stabilization. This paper does not establish roles in synaptic plasticity or network activity; the sentence separately cites [23] for DNA/RNA stability. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] source

      The Discussion and the section on synaptic mitochondria describe effects of tau deletion on cytoskeletal proteins, synapses, and mitochondrial localization under stress. Our copy does not establish a role in network activity. DNA/RNA stability is attached to a separate citation [23] in the citing sentence, so it is not assessed against this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] 2014, Selective impact of Tau loss on nociceptive primary afferents and pain sensation, Exp Neurol source
  • Premisecitation

    In some PD models, tau removal improves aberrant network activity.

    “Some PD models showed improvements in aberrant network activity upon tau removal [82]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [82] Peters, S.T. , et al., Ablating Tau Reduces Hyperexcitability and Moderates Electroencephalographic Slowing in Transgenic Mice Expressing A53T Human α-Synuclein. Frontiers in Neurology, 2020. Volume 11 - 2020. source
  • Premisecitation

    In multiple mouse disease models, tau ablation is associated with protective effects.

    “Interestingly, in multiple mouse disease models, tau ablation has been associated with protective effects.”
    Quote in the paperSubstantial claim7 of 9 sources checked
    • cites [75] Roberson, E.D. , et al., Reducing Endogenous Tau Ameliorates Amyloid β-Induced Deficits in an Alzheimer’s Disease Mouse Model. Science, 2007. 316(5825): p. 750-754. source
    • cites [76] source
    • cites [77] source
    • cites [78] source
    • cites [79] source
    • cites [56] 2020, Tau Reduction Prevents Key Features of Autism in Mouse Models, Neuron source
    • cites [80] 2023, Tau reduction attenuates autism-like features in Fmr1 knockout mice, Mol Autism source
    • cites [81] Shao, E. , et al., TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model. Science Translational Medicine, 2022. 14(642): p. eabm5527. source
    • cites [82] Peters, S.T. , et al., Ablating Tau Reduces Hyperexcitability and Moderates Electroencephalographic Slowing in Transgenic Mice Expressing A53T Human α-Synuclein. Frontiers in Neurology, 2020. Volume 11 - 2020. source
  • Classified as probably not a substantial claim. 9
  • May combine two claims. 49
  • The quote only partly states this claim. 2

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

    Premisecitation

    Tau is a microtubule-associated protein that stabilizes microtubules by interacting with tubulin heterodimers, supporting axonal structure and neuronal morphology.

    “The microtubule-associated protein tau (MAPT) was first identified as a key regulator of microtubule stability and assembly [1]. Tau stabilizes microtubules by interacting with tubulin heterodimers, thereby supporting axonal structure and maintaining neuronal morphology [2–4].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [1] source

      The paper’s introduction and Discussion identify tau as a protein essential for in vitro microtubule assembly and describe its association with tubulin dimers. The Discussion distinguishes assembly from stability and says tau’s actual in vivo function is unknown. It therefore does not establish that tau stabilizes microtubules or supports axonal structure and neuronal morphology. Page numbers are not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [2] source
    • cites [3] source
    • cites [4] source

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

    Premisecitation

    Tau is predominantly expressed in cortical and hippocampal neurons, with expression also in oligodendrocytes and astrocytes.

    “Tau is predominantly expressed in cortical and hippocampal neurons [5–7], although there is also expression in other cell types such as oligodendrocytes and astrocytes [8, 9].”
    Quote in the paperNot a substantial claim3 of 5 sources checked
    • cites [5] 2022, Distribution of five clinically important neuroglial proteins in the human brain, Molecular Brain source

      The citation is attached to the claim that tau is expressed in oligodendrocytes and astrocytes. The Results (Distribution of neuroglial proteins; page unavailable) measure tau in anatomical tissue regions, not individual cell types. Searches for oligodendrocytes, astrocytes, and glial expression found no passage addressing that claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [6] 2023, Tau; One Protein, So Many Diseases, Biology source
    • cites [7] source

      The Results (p. 1374) locate tau mainly in neuronal axons, supporting the neuronal part of the claim. The paper examines the medulla, substantia nigra, and cerebellum, but does not establish predominant expression in cortical or hippocampal neurons. The glial-cell clause has separate citations [8, 9] and is not attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [8] source
    • cites [9] 1987, Phosphorylation determines two distinct species of tau in the central nervous system, Cell Motility source

  • May combine two claims.

    Premisecitation

    Tau ablation is beneficial in a mouse model of cerebral amyloid angiopathy (CAA), reducing vascular damage and improving behavioral outcomes.

    “Moreover, we recently demonstrated that tau ablation is beneficial in a mouse model of cerebral amyloid angiopathy (CAA), reducing vascular damage and improving behavioral outcomes [85].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] 2025, Tau depletion diminishes vascular amyloid-related deficits in a mouse model of cerebral amyloid angiopathy, Alzheimer’s & Dementia source

  • May combine two claims.

    Premisecitation

    Tau ablation improves outcomes in models of TBI and high-salt diet-induced vascular dysfunction, with improvements in cognitive performance.

    “Beyond neurodegenerative and neurodevelopmental disorders, tau ablation has also been shown to improve outcomes in models of neurological injury and vascular stress, such TBI and high-salt diet-induced vascular dysfunction, with associated improvements in cognitive performance [72, 86, 87].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [72] source

      The Results section on p300/CBP inhibition reports that reducing acetylated tau after TBI protected mice from learning and memory deficits. It says this treatment did not change total tau, so it does not establish an effect of tau ablation. No passage found on high-salt diet-induced vascular dysfunction (searched: high-salt diet, vascular dysfunction, tau ablation); the indexed passages have no page numbers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [86] source
    • cites [87] Faraco, G. , et al., Dietary salt promotes cognitive impairment through tau phosphorylation. Nature, 2019. 574(7780): p. 686-690. source

  • May combine two claims.

    Premisecitation

    In AD models, absence of tau rescues behavioral impairments and reduces neurotoxicity despite no significant changes in Aβ levels.

    “For example, in AD models, the absence of tau has been shown to rescue behavioral impairments and reduce neurotoxicity, despite no significant changes in Aβ levels [75–79].”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [75] Roberson, E.D. , et al., Reducing Endogenous Tau Ameliorates Amyloid β-Induced Deficits in an Alzheimer’s Disease Mouse Model. Science, 2007. 316(5825): p. 750-754. source
    • cites [76] source

      The Results section on behavioral abnormalities reports that tau-absent hAPPJ9/Fyn mice performed better on learning and memory tests, and the Discussion section on synaptic effects reports that tau reduction corrected neuronal dysfunction in hAPPJ20 mice (page numbers unavailable). However, the passages do not establish that these benefits occurred without significant changes in Aβ levels, or demonstrate reduced neuronal death if “neurotoxicity” means cell death. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [77] source
    • cites [78] source

      The Results section reports that tau ablation prevented Aβ-associated axonal transport deficits in cultured neurons without altering Aβ levels in their growth medium. The Introduction also describes prior evidence linking tau to Aβ-induced cell death and behavioral alterations. But this paper does not show that tau absence rescues behavioral impairments or reduces neurotoxicity in AD models; its direct finding concerns axonal transport. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [79] source

      The Abstract reports that tau deletion rescued memory and motor impairments, neuronal loss, and synaptic loss in APP/PS1 mice. But it also reports reduced soluble and insoluble Aβ40 and Aβ42; the Discussion describes an approximately 50% decrease in amyloid burden. Thus this paper does not support the claim that these benefits occurred without significant changes in Aβ levels. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In HD models, tau ablation reduces motor abnormalities and restores neurite length.

    “while in HD models, ablation led to reduced motor abnormalities and restoration of neurite length [83, 84].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [83] source

      The Results report reduced motor impairment in CP13-treated HD mice, and the Discussion reports that CP13 rescued neurite retraction in HD-derived neurons. But CP13 is an antibody treatment, not tau ablation. The Discussion separately describes improved motor features after reduced Mapt expression in an earlier study; it does not link ablation to the neurite-length result. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [84] source

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

    Premisecitation

    Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.

    “Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
    Quote in the paperSubstantial claim5 of 10 sources checked
    • cites [37] source
    • cites [38] source
    • cites [39] source
    • cites [40] source
    • cites [41] source

      The Discussion (page unavailable) links dysregulation of tau’s normal function to neuronal pathology and describes hyperphosphorylation, neurofibrillary tangles, and missorting into somatodendrites. The Introduction (page unavailable) also associates tau accumulation with synapse and neuron loss. The paper does not establish gain of toxic function as a distinct mechanism, so it does not support the full four-part claim. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [42] source

      The Discussion describes impaired microtubule stabilization as a loss of function and increased, potentially toxic tau oligomers as a gain of function; it also discusses aggregation. These findings concern the p.A152T variant, and no passage in our copy supports mislocalization as a mechanism (searched: mislocalization of tau). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [43] source
    • cites [44] source
    • cites [45] source
    • cites [46] source

  • May combine two claims.

    Premisecitation

    In ASD models, tau knockdown is associated with reduced autistic-like behaviors and decreased seizure susceptibility.

    “In models of ASD, tau knockdown has been associated with reduced autistic-like behaviors and decreased seizure susceptibility [56, 80, 81].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [56] 2020, Tau Reduction Prevents Key Features of Autism in Mouse Models, Neuron source
    • cites [80] 2023, Tau reduction attenuates autism-like features in Fmr1 knockout mice, Mol Autism source

      The Discussion reports that genetic and antisense-mediated tau reduction alleviated social deficits and repetitive behaviors in Fmr1 knockout mice, supporting the behavioral part of the claim. The paper does not report a seizure-susceptibility outcome in those mice; its references include other studies on tau reduction and seizures, but that does not establish the claimed outcome for this study. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [81] Shao, E. , et al., TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model. Science Translational Medicine, 2022. 14(642): p. eabm5527. source

  • May combine two claims.

    Premisecitation

    Tg-FDD mice present motor impairment, vascular damage, astrocytic reactivity and altered inflammation pathways in a sex dependent manner, with males exhibiting stronger phenotype.

    “Mice present motor impairment, vascular damage, astrocytic reactivity and altered inflammation pathways in a sex dependent manner, with males exhibiting stronger phenotype [85].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [85] 2025, Tau depletion diminishes vascular amyloid-related deficits in a mouse model of cerebral amyloid angiopathy, Alzheimer’s & Dementia source

      The Results sections on motor strength, vascular damage, and astrocytic reactivity report reduced grip strength in Tg-FDD mice, while vascular damage and astrocytic reactivity were observed only in males. The inflammation Results report altered inflammatory genes and pathways, but that analysis included only males; the reported motor-strength findings also do not establish a stronger male phenotype. Thus, the source does not support applying the sex-dependent, stronger-in-males description to all four findings. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Astrocytes are key regulators of synaptic homeostasis, metabolic support, and neuroinflammation, and are implicated in neurodegenerative disease processes.

    “Astrocytes, as key regulators of synaptic homeostasis, metabolic support, and neuroinflammation, are particularly sensitive to changes in the neuronal environment and have been implicated in numerous neurodegenerative disease processes [112–114].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [112] 2025, Mechanisms of astrocyte aging in reactivity and disease, Molecular Neurodegeneration source
    • cites [113] source
    • cites [114] source

  • Classified as probably not a substantial claim.

    Premisecitation

    Tau is expressed in non-neuronal cells.

    “Tau is known to also been express in non-neuronal cells [108–111] (Supplementary Figure 2A–B).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [108] 2024, Tau here, tau there, tau almost everywhere: Clarifying the distribution of tau in the adult CNS, Cytoskeleton source
    • cites [109] Kanaan, N.M. and T. Grabinski , Neuronal and Glial Distribution of Tau Protein in the Adult Rat and Monkey. Frontiers in Molecular Neuroscience, 2021. Volume 14 - 2021. source
    • cites [110] source
    • cites [111] source

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [56] 2020, Tau Reduction Prevents Key Features of Autism in Mouse Models, Neuron source

      The Results (page unavailable) report that tau ablation prevented autism-like behavioral deficits and that tau reduction prevented neural abnormalities in two neurodevelopmental mouse models. The Discussion (page unavailable) mentions benefits in neurodegenerative models but does not establish neuronal protection as the cause of behavioral recovery across both types of model. This study primarily demonstrates prevention of deficits, not recovery after they develop. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [75] Roberson, E.D. , et al., Reducing Endogenous Tau Ameliorates Amyloid β-Induced Deficits in an Alzheimer’s Disease Mouse Model. Science, 2007. 316(5825): p. 750-754. source
    • cites [76] source

      The Results section reports that tau ablation improved learning and memory performance in hAPPJ9/Fyn mice, supporting protection against behavioral deficits in an Alzheimer’s disease model. The Discussion limits the benefit to specific AD-related circumstances: it reports no benefit in an ALS model and adverse effects in a Niemann–Pick type C model. This paper does not establish the claim across neurodevelopmental models. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [121] DeVos, S.L. , et al., Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med, 2017. 9(374). source

      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
    • cites [122] source

      The Results section, “Reducing tau decreases hyperexcitability in bang-sensitive Drosophila mutants” (page unavailable), reports fewer seizure-like behaviors and paralysis after tau reduction; the Discussion also reports reduced seizures in Kcna1−/− mice. But the paper does not establish that neuronal protection caused recovery of behavioral deficits: it says tau loss *may* be neuroprotective and clarifies that its experiments tested absence of tau during development, not reversal of a preexisting disorder. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [123] source

      The Results section (page unavailable) reports that tau ablation prevented memory deficits in Scn1aRX/+ Dravet mice, and the Discussion reports improvements in other behaviors. This supports behavioral improvement in a neurodevelopmental model, but the paper does not establish that neuronal protection caused those improvements; it instead proposes reduced epileptic activity as an explanation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    SLC1A2 (GLT-1) is the principal mediator of extracellular L-glutamate uptake, predominantly expressed in astrocytes but also present in excitatory neuronal terminals.

    “SLC1A2 (also known as GLT-1) is the principal mediator of extracellular L-glutamate uptake, predominantly expressed in astrocytes but also present in excitatory neuronal terminals [106, 125].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [106] source
    • cites [125] source

  • May combine two claims.

    Premisecitation

    Tau can regulate PI3K-Akt-mTOR signaling, but under pathological stress such as in ASD or amyloid accumulation, it can promote network dysfunction.

    “Tau can regulate this pathway [56], but under pathological stress such as in conditions such as ASD or amyloid accumulation, it can promote network dysfunction [22, 143].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [56] 2020, Tau Reduction Prevents Key Features of Autism in Mouse Models, Neuron source

      The Discussion (page not provided) proposes that tau enables abnormalities in some ASD mouse models under pathological conditions, supporting the ASD portion of the claim. Our copy does not establish the amyloid-accumulation portion; amyloid-related network impairment appears in the title of another study in the References, not as a finding of this study. The PI3K/Akt/mTOR clause is attached to a different citation in the citing sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Chang, C.-W. , et al., Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony. Cell Reports, 2021. 37(3). source
    • cites [143] Chang, C.W. , E. Shao , and L. Mucke , Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science, 2021. 371(6532). source

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

    Premisecitation

    Loss or dysfunction of SLC1A2 has been implicated in multiple neurodegenerative and neuropsychiatric disorders, including AD where it is closely associated with cognitive decline.

    “Loss or dysfunction of SLC1A2 has been implicated in multiple neurodegenerative and neuropsychiatric disorders, including AD where it is closely associated with cognitive decline [126–131].”
    Quote in the paperNot a substantial claim4 of 6 sources checked
    • cites [126] 2024, Common and divergent pathways in early stages of glutamate and tau-mediated toxicities in neurodegeneration, Experimental Neurology source

      The Introduction (page unavailable) identifies SLC1A2 as EAAT2/GLT-1, reports its deficiency in AD brains, and says GLT-1 deficiency accelerated cognitive decline in mice. The Discussion (page unavailable) also links reduced GLT-1 to AD and reports improved cognitive markers after GLT-1 overexpression in AD mouse models. These passages support an AD-related connection, but do not establish a close association with cognitive decline in people with AD or implicate SLC1A2 dysfunction in multiple neuropsychiatric disorders. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [127] 2022, Gene variations of glutamate metabolism pathway and epilepsy, Acta Epileptologica source

      The Glutamate transport section links SLC1A2 mutations to developmental epileptic encephalopathy and reports progressive neuronal death in knockout mice. It does not link SLC1A2 to multiple neurodegenerative or neuropsychiatric disorders, Alzheimer’s disease, or cognitive decline. In the Conclusions table, “AD” means autosomal dominant, not Alzheimer’s disease; no page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [128] 2007, Alterations in Expression of Glutamatergic Transporters and Receptors in Sporadic Alzheimer’s Disease, Journal of Alzheimer’s Disease source
    • cites [129] source
    • cites [130] source

      The Discussion (page unavailable) links SLC1A2 to tau pathology in Alzheimer’s disease and reports that lower expression in astrocytes and neurons was associated with worse cognitive performance. It does not address SLC1A2 loss or dysfunction across multiple neurodegenerative and neuropsychiatric disorders, so that broader part of the claim is unsupported by this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [131] source

      Our indexed copy contains only a garbled title and section headings, with no substantive passages to assess this claim. Searches for Alzheimer’s disease, cognitive decline, and SLC1A2 dysfunction found no relevant text, so the copy cannot establish whether the paper supports the attributed association. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Once tau is eliminated, glia appear better able to mount context and disease-appropriate responses, including elimination of toxic species, reduction in kinase activation, and modulation of downstream signaling, potentially explaining the broad protective effects of tau ablation across pathological models.

    “Once tau is eliminated, glia appear better able to mount context and disease-appropriate responses, including elimination of toxic species [144], reduction in kinase activation, and modulation of downstream signaling [76, 78, 145], potentially explaining the broad protective effects of tau ablation across pathological models.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [144] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [76] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [78] source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [145] source
    • Rests on an assumption: Tau is eliminated from all cell types in the global knockout.

  • Classified as probably not a substantial claim.

    Premisecitation

    The literature has established a role for tau in regulating glutamatergic synaptic function, where it interacts with Fyn, NMDARs, PSD-95, and SynGAP1.

    “The literature has established a role for tau in regulating glutamatergic synaptic function, where it interacts with Fyn, NMDARs, PSD-95, and SynGAP1 [41, 77, 105].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [41] source

      The Discussion reports that tau is required for hippocampal long-term depression, supporting a role in synaptic function. The Results place tau in a PSD-95-rich fraction, and the Discussion says NMDAR activation can affect its localization, but neither establishes direct interaction with PSD-95 or NMDARs. The searched passages do not support interactions with Fyn or SynGAP1. Page numbers were not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [77] source
    • cites [105] source

  • May combine two claims.

    Premisecitation

    Tau misfolds and acquires toxic gain-of-function properties in our vascular amyloid model.

    “Given that microglia can phagocytose extracellular pathological tau [148, 149], and that tau misfolds and acquires toxic gain-of-function properties in our vascular amyloid model [120], tau ablation likely reduces this pathological burden.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [120] 2019, Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy, Acta Neuropathologica Communications source

      The Results (page not available) show increased misfolded tau in Tg-FDD mice, and the Discussion reports that ADan oligomers cause tau-dependent cellular toxicity and synaptic impairment. The paper does not establish that misfolded tau itself acquires a toxic gain of function in the vascular amyloid model; tau dependence does not distinguish that from a role for normal tau. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Findingown data

    The proportion of Excitatory Neuron 12 (ExNeuron12) cells was uniquely increased in Mapt−/− mice compared to WT.

    “The proportion of cells in Excitatory Neuron 12 (ExNeuron12) was uniquely expressed in the Mapt−/− model compared to wild type.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    snRNA-seq on cortices of aged Mapt−/− mice in WT background revealed genotype-dependent changes across multiple brain cell types under physiological conditions.

    “Our results revealed genotype-dependent changes across multiple brain cell types under physiological conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Differential gene expression analysis between WT and Mapt−/− microglia revealed significant transcriptional changes, with 137 Mapt−/−-specific DEGs enriched in synaptic pathways including chemical synaptic transmission, anterograde trans-synaptic signaling, synapse organization, and protein-protein interaction at synapses.

    “While tau ablation does not impact cell composition, differential gene expression analysis between WT and Mapt−/− microglia still revealed significant transcriptional changes, with a set of Mapt−/−-specific DEGs (137 Blue Genes) enriched in pathways relevant to synaptic terms, i.e. chemical synaptic transmission, anterograde trans-synaptic signaling, synapse organization, and protein-protein inter”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cell type proportion analysis across excitatory and inhibitory neurons showed that only excitatory neurons exhibited significant genotype-dependent changes, with a marked expansion of the Excitatory Neuron 6 (ExNeuron6) cluster in Tg-FDD;Mapt−/− brains.

    “Cell type proportion analysis across excitatory and inhibitory neurons showed that only excitatory neurons exhibited significant genotype-dependent changes, with a marked expansion of the Excitatory Neuron 6 (ExNeuron6) cluster in Tg-FDD;Mapt−/− brains (Fig. 5B–C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although astrocytes, oligodendrocytes, and microglia maintained stable proportions in Tg-FDD;Mapt−/− mice, they exhibited restoration of gene programs that were disrupted in Tg-FDD mice.

    “Although astrocytes, oligodendrocytes, and microglia maintained stable proportions, they exhibited restoration of gene programs that were disrupted in Tg-FDD mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although the overall inferred communication landscape was reduced, pathway-level chord plots revealed persistent selective increases in synaptic and neurotransmitter-related signaling within these clusters.

    “Although the overall inferred communication landscape was reduced, pathway-level chord plots of the previously mentioned clusters revealed persistent selective increases in synaptic and neurotransmitter-related signaling within these clusters (Fig. 8C–D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CellChat inferred communications based on coordinated expression of ligands, receptors, and cofactors reflect actual intercellular communication.

  • May combine two claims.

    Findingown data

    Functional enrichment of the oligodendrocyte (Y) set showed pathways centered on phagocytic activity, including FCGR-dependent engulfment, actin remodeling for phagocytic cup formation, and regulation of RHO/RAS/MAPK signaling, and terms encompassing regulation of neuron projection growth and myelination.

    “Functional enrichment of the (Y) set (Fig. 7F) showed pathways centered on phagocytic activity, including FCGR-dependent engulfment, actin remodeling for phagocytic cup formation, and regulation of RHO/RAS/MAPK signaling. Additional terms encompassed regulation of neuron projection growth, and myelination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Non-neuronal populations were also affected: astrocytes displayed heterogeneity with the emergence of a subcluster with protective features.

    “Non-neuronal populations were also affected: astrocytes displayed heterogeneity with the emergence of a subcluster with protective features.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Applying the 3D volcano plot framework on the microglia subcluster identified 13 genes associated to (R) set upregulated only in Tg-FDD;Mapt−/− and 4 genes in the (Y) set that were selectively upregulated in both Tg-FDD;Mapt−/− and WT but not in Tg-FDD microglia.

    “Applying the 3D volcano plot framework on the microglia subcluster (subcluster 0; 1383 cells; Supplementary Fig. 5D) identified 13 genes associated to (R) set upregulated only in Tg-FDD;Mapt−/− and 4 genes in the (Y) set that were selectively upregulated in both Tg-FDD;Mapt−/− and WT but not in Tg-FDD microglia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tau removal in a CAA model produced a distinct set of changes, with excitatory neurons responding with an expansion of ExNeuron6.

    “In contrast, tau removal in a CAA model produced a distinct set of changes. Excitatory neurons responded with an expansion of ExNeuron6.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Astrocyte, oligodendrocyte, and microglia subcluster proportions remained stable upon tau loss in the Tg-FDD model, although each exhibited disease-specific transcriptional remodeling.

    “Astrocyte, oligodendrocyte, and microglia subcluster proportions remained stable upon tau loss in the Tg-FDD model, although each exhibited disease-specific transcriptional remodeling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the Tg-FDD vascular amyloid context, tau ablation reduced overall predicted intercellular communication while selectively preserving or enhancing synaptic signaling within neuronal and glial clusters.

    “In contrast, in the Tg-FDD vascular amyloid context, tau ablation reduced overall predicted intercellular communication while selectively preserving or enhancing synaptic signaling within neuronal and glial clusters.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CellChat inferred communications based on coordinated expression of ligands, receptors, and cofactors reflect actual intercellular communication.
    • Rests on an assumption: The amyloid insult persists in the Tg-FDD;Mapt−/− model.

  • May combine two claims.

    Findingown data

    Across multiple cell types, tau removal induced 'Tg-FDD;Mapt−/− unique' (R) gene sets, representing transcriptional changes that emerged independently of disease-associated dysregulation and were not altered in Tg-FDD versus WT conditions.

    “Across multiple cell types, tau removal induced “Tg-FDD;Mapt−/− unique” (R) gene sets, representing transcriptional changes that emerged independently of disease-associated dysregulation and were not altered in Tg-FDD versus WT conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The altered outgoing and incoming glutamatergic communication observed for ExNeuron12 is consistent with synaptic homeostasis and protection against excitotoxic stress.

    “Together, these findings suggest that the altered outgoing and incoming glutamatergic communication observed for ExNeuron12 is consistent with synaptic homeostasis and protection against excitotoxic stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The expansion of the excitatory neuron subtype in Tg-FDD;Mapt−/− mice suggests compensatory synaptic plasticity and rewired excitatory connectivity.

    “suggesting compensatory synaptic plasticity and rewired excitatory connectivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Oligodendrocytes may respond to tau loss by modulating genes important for neuronal connectivity and function, potentially supporting neuroprotection or compensating for altered neuronal signaling.

    “Our oligodendrocyte results suggest that this type of glia may respond to tau loss by modulating genes important for neuronal connectivity and function, potentially supporting neuroprotection or compensating for altered neuronal signaling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Tau absence in astrocytes suggests altered neuron-astrocyte interactions and potential shifts in astrocytic support of excitatory neurotransmission.

    “suggesting altered neuron-astrocyte interactions and potential shifts in astrocytic support of excitatory neurotransmission”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    The distinct enrichment of neuroprotective genes in subcluster 4 potentially reflects activation of heightened protective mechanisms in response to absence of physiological tau.

    “potentially reflecting the activation of heightened protective mechanisms in response to the absence of physiological tau.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These changes do not primarily reflect restoration of disease-associated transcriptional alterations observed in Tg-FDD mice, but instead represent a distinct Tg-FDD;Mapt−/−-specific neuronal state characterized by induction of genes not significantly dysregulated in Tg-FDD versus WT conditions.

    “Notably, these changes do not primarily reflect restoration of disease-associated transcriptional alterations observed in Tg-FDD mice, but instead represent a distinct Tg-FDD;Mapt−/−-specific neuronal state characterized by induction of genes not significantly dysregulated in Tg-FDD versus WT conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These enrichments suggest reinforcement and support of neuronal connectivity, synaptic modulation, and intracellular transcriptional regulation.

    “Together, these enrichments suggest reinforcement and support of neuronal connectivity, synaptic modulation, and intracellular transcriptional regulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Tau loss drives microglia toward a transcriptional state associated with synaptic interaction and structural remodeling, implying modified microglial contributions to synaptic maintenance in the healthy aged brain.

    “These findings indicate that tau loss drives microglia toward a transcriptional state associated with synaptic interaction and structural remodeling, implying modified microglial contributions to synaptic maintenance in the healthy aged brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Endogenous tau ablation in a vascular disease context selectively restores astrocytic transcriptional programs toward a WT-like state without broadly altering astrocyte subpopulation composition.

    “Together, these results demonstrate that endogenous tau ablation in a vascular disease context selectively restores astrocytic transcriptional programs toward a WT-like state without broadly altering astrocyte subpopulation composition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These enrichments indicate restoration of metabolic support and extracellular signaling programs that are disrupted in Tg-FDD astrocytes.

    “These enrichments indicate restoration of metabolic support and extracellular signaling programs that are disrupted in Tg-FDD astrocytes (Fig. 6F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Changes in oligodendrocytes and microglia with endogenous tau ablation in a vascular disease context are transcriptional rather than compositional, with partial restoration of microglial transcriptional programs toward WT-like states.

    “Together, these findings indicate that changes in oligodendrocytes and microglia with endogenous tau ablation in a vascular disease context are transcriptional rather than compositional, with partial restoration of microglial transcriptional programs toward WT-like states.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Removal of endogenous tau not only attenuates pathways that sensitize neurons to excitotoxic stress but also promotes compensatory engagement of glutamate clearance mechanisms, thereby enhancing excitotoxic stress resilience in the absence of physiological tau.

    “Taken together, these observations suggest that removal of endogenous tau not only attenuates pathways that sensitize neurons to excitotoxic stress but also promotes compensatory engagement of glutamate clearance mechanisms, thereby enhancing excitotoxic stress resilience in the absence of physiological tau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Our findings suggest a shift from tau-driven excitotoxic amplification toward mechanisms that promote glutamate buffering and synaptic homeostasis, consistent with enhanced SLC1A2-associated glutamatergic regulation.

    “Our findings suggest a shift from tau-driven excitotoxic amplification toward mechanisms that promote glutamate buffering and synaptic homeostasis, consistent with enhanced SLC1A2-associated glutamatergic regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Tau is a context-dependent regulator of brain cellular communication programs, where its ablation induces distinct transcriptional and intercellular rewiring in non-disease aging versus vascular amyloid pathology.

    “Here we identify tau as a context-dependent regulator of brain cellular communication programs, where its ablation induces distinct transcriptional and intercellular rewiring in non-disease aging versus vascular amyloid pathology.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: It is still unclear mechanistically how tau removal exerts its protective effects at the cellular and molecular level and which cells are involved in restoring or rewiring transcriptional programs and intercellular communication pathways.

  • May combine two claims.

    Interpretationown data

    In the presence of vascular amyloid pathology, tau ablation dampens the global intercellular communication network while selectively enhancing synaptic signaling pathways.

    “Together, these results suggest that in the presence of vascular amyloid pathology, tau ablation dampens the global intercellular communication network while selectively enhancing synaptic signaling pathways.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CellChat inferred communications based on coordinated expression of ligands, receptors, and cofactors reflect actual intercellular communication.
    • Rests on an assumption: The amyloid insult persists in the Tg-FDD;Mapt−/− model.

  • May combine two claims.

    Interpretationreasoning

    The impact of tau deletion differs fundamentally between physiological and pathological environments, likely reflecting compensatory or adaptive mechanisms engaged in response to amyloid-driven network disruption.

    “This context-dependent remodeling of communication networks underscores that the impact of tau deletion differs fundamentally between physiological and pathological environments, likely reflecting compensatory or adaptive mechanisms engaged in response to amyloid-driven network disruption.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CellChat inferred communications based on coordinated expression of ligands, receptors, and cofactors reflect actual intercellular communication.
    • Rests on an assumption: The amyloid insult persists in the Tg-FDD;Mapt−/− model.

  • May combine two claims.

    Interpretationown data

    Tau ablation alone triggers compensatory remodeling and reduces intrinsic excitotoxic vulnerability, but in disease settings this protective effect becomes more evident.

    “Our data presents the following paradigm; tau ablation alone triggers compensatory remodeling and reduces intrinsic excitotoxic vulnerability. However, in disease settings, this protective effect becomes more evident.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The oligodendrocyte population regains processes for debris clearance, intracellular signaling modulation, and support of neuronal structure and myelin integrity.

    “All of these suggest that the oligodendrocyte population regains processes for debris clearance, intracellular signaling modulation, and support of neuronal structure and myelin integrity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These findings suggest a complementary model of benefit: neurons are directly protected by removal of tau's toxic gain of function, while glial populations likely benefit both from reduced neuronal dysfunction and intrinsic consequences of tau deletion within glial cells.

    “These findings suggest a complementary model of benefit: neurons are directly protected by removal of tau’s toxic gain of function, while glial populations likely benefit both from reduced neuronal dysfunction and intrinsic consequences of tau deletion within glial cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Removal of tau and its amyloid-induced toxic gain-of-function, together with a rebalancing of excitatory signaling, enables a shift away from maladaptive processes in the disease setting.

    “Although the amyloid insult persists, removal of tau and its amyloid-induced toxic gain-of-function, together with a rebalancing of excitatory signaling reflected by the enrichment of genes associated with glutamatergic synaptic transmission, enables a shift away from maladaptive processes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The amyloid insult persists in the Tg-FDD;Mapt−/− model.

  • May combine two claims.

    Interpretationreasoning

    While neuronal benefits largely reflect cell-autonomous removal of toxic tau functions, glial benefits likely arise from both intrinsic tau loss and relief of external tau-enabled dysregulation.

    “While neuronal benefits largely reflect cell-autonomous removal of toxic tau functions, glial benefits likely arise from both intrinsic tau loss and relief of external tau-enabled dysregulation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau is eliminated from all cell types in the global knockout.

  • May combine two claims.

    Interpretationreasoning

    Tau deletion appears to remodel signaling networks in a state-dependent manner, broadly potentiating synaptic interactions in physiology while dampening maladaptive global signaling and refining essential pathways under pathological stress.

    “Thus, rather than uniformly amplifying communication, tau deletion appears to remodel signaling networks in a state-dependent manner. It broadly potentiates synaptic interactions in physiology while dampening maladaptive global signaling and refining essential pathways under pathological stress.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CellChat inferred communications based on coordinated expression of ligands, receptors, and cofactors reflect actual intercellular communication.

  • May combine two claims.

    Interpretationreasoning

    Neuronal responses to tau loss primarily reflected adaptive remodeling and emergence of new cellular states, while glial responses reflected recovery of disease-associated dysfunction.

    “Thus, while neuronal responses to tau loss primarily reflected adaptive remodeling and emergence of new cellular states, glial responses reflected recovery of disease-associated dysfunction.”
    Quote in the paperSubstantial claim
54 of 54

  • The paper relies on this without support.

    The cellular and molecular mechanisms underlying the protection conferred by tau depletion remain poorly understood.

    “Despite these consistent protective effects, the cellular and molecular mechanisms underlying the protection conferred by tau depletion remain poorly understood.”

  • The paper relies on this without support.

    Mapt−/− mice lack functional tau protein.

    “tau knockout (Mapt−/−) mice”

  • The authors state this as an assumption.

    It is still unclear mechanistically how tau removal exerts its protective effects at the cellular and molecular level and which cells are involved in restoring or rewiring transcriptional programs and intercellular communication pathways.

    “However, it is still unclear mechanistically how tau removal exerts these many protective effects at the cellular and molecular level and which cells are involved in restoring or rewiring transcriptional programs and intercellular communication pathways.”

  • The paper relies on this without support.

    CellChat inferred communications based on coordinated expression of ligands, receptors, and cofactors reflect actual intercellular communication.

    “we performed ligand-receptor analysis using CellChat, which infers communications based on the coordinated expression of ligands, receptors, and cofactors [97].”

  • The paper relies on this without support.

    Tau is eliminated from all cell types in the global knockout.

    “Because tau is eliminated from all cell types in the global knockout, glial transcriptional remodeling may reflect both cell-autonomous and non-cell-autonomous mechanisms whereby relief of neuronal stress reduces maladaptive signaling and enables glia to re-engage adaptive programs [143].”

  • The paper relies on this without support.

    The amyloid insult persists in the Tg-FDD;Mapt−/− model.

    “Although the amyloid insult persists, removal of tau and its amyloid-induced toxic gain-of-function, together with a rebalancing of excitatory signaling reflected by the enrichment of genes associated with glutamatergic synaptic transmission, enables a shift away from maladaptive processes.”
6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. 10.1016/j.neurobiolaging.2014.05.005 · DOI · Paper page
  2. 10.3389/fnmol.2021.607303 · DOI · Paper page
  3. 10.1016/j.cell.2010.06.036 · DOI · Paper page

Authors
Chimal-Juárez, E., Patel, H., Jury-Garfe, N., Dabin, L. C., Vidal, R., Kim, J., & Lasagna-Reeves, C. A.
Affiliations
  • Department of Neurology, Baylor College of Medicine, Houston, TX, USA
  • Baylor College of Medicine (US)
  • Indiana University Indianapolis (US)
  • Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
ORCID
Venue
bioRxiv
Publisher
openRxiv
Published
2026-05-17
DOI
10.64898/2026.05.12.724684
PMC
PMC13192590
OpenAlex
W7161509106
Semantic Scholar
4f23307aaeefecbdccda046ce264d82dfa6eb689
Cited by
0
References
146
Type
posted content
Language
en
Open access
Licence
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
Funders
  • NIH/NINDS (1R01NS119280)
  • NIH/NIA (1RF1AG059639)
  • Alzheimer's Association (ALZDISCOVERY-1049108)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tau knockout mice, single-nucleus RNA sequencing, cortical cell types, excitatory neurons, astrocytes, oligodendrocytes, microglia, neurodegeneration, glutamatergic signaling, myelin integrity, postsynaptic signaling

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 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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