CoChat
Sign Up
Cited by 105Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity

Open access
Ando, Kanae, Maruko-Otake, Akiko, Ohtake, Yosuke, Hayashishita, Motoki, Sekiya, Michiko, Iijima, Koichi M.·2016·PLOS Genetics
DOI 10.1371/journal.pgen.1005917PMC PMC4811436
Open this paper in CoChat — free accountOpen PDF

Abstract

Abnormal accumulation of the microtubule-interacting protein tau is associated with neurodegenerative diseases including Alzheimer's disease (AD). β-amyloid (Aβ) lies upstream of abnormal tau behavior, including detachment from microtubules, phosphorylation at several disease-specific sites, and self-aggregation into toxic tau species in AD brains. To prevent the cascade of events leading to neurodegeneration in AD, it is essential to elucidate the mechanisms underlying the initial events of tau mismetabolism. Currently, however, these mechanisms remain unclear. In this study, using transgenic Drosophila co-expressing human tau and Aβ, we found that tau phosphorylation at AD-related Ser262/356 stabilized microtubule-unbound tau in the early phase of tau mismetabolism, leading to neurodegeneration. Aβ increased the level of tau detached from microtubules, independent of the phosphorylation status at GSK3-targeted SP/TP sites. Such mislocalized tau proteins, especially the less phosphorylated species, were stabilized by phosphorylation at Ser262/356 via PAR-1/MARK. Levels of Ser262 phosphorylation were increased by Aβ42, and blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231, suggesting that this process may be involved in AD pathogenesis. In contrast to PAR-1/MARK, blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity. These results suggest that stabilization of microtubule-unbound tau by phosphorylation at Ser262/356 via the PAR-1/MARK may act in the initial steps of tau mismetabolism in AD pathogenesis, and that such tau species may represent a potential therapeutic target for AD.

AI snapshot

Written from the paper’s full text.

TL;DR

In transgenic Drosophila co-expressing human tau and Aβ42, Aβ42 increases cytosolic microtubule-unbound tau, and PAR-1/MARK phosphorylation of tau at Ser262/356 stabilizes less-phosphorylated tau (taulower), contributing to Aβ42-induced tau toxicity and increased pThr231. Blocking this phosphorylation suppresses Aβ42-mediated augmentation of tau toxicity, whereas GSK3/Sgg SP/TP phosphorylation is not required for tau mislocalization or toxicity in this model.

Key findings

  • Aβ42 co-expression increased tau in the cytosol and reduced microtubule-bound tau without changing total tau levels; both tauupper and taulower shifted, and a higher-Aβ42-expressing line showed a larger effect (Fig 1).
  • S2A mutation at Ser262/356 preferentially reduced taulower and partially suppressed Aβ42-mediated mislocalization: Aβ42 caused a 3-fold increase in wild-type tauupper in the cytosol but only a 1.6-fold increase in S2A tauupper; S2A also blocked Aβ42-induced increases in pThr231 and suppressed tau-mediated eye degeneration (Figs 3 and 7).
  • PAR-1 knockdown reduced taulower and pSer262, while PAR-1 overexpression increased taulower and pThr231; these effects required Ser262/356, as PAR-1 did not alter S2A tau levels. Aβ42 increased pSer262, and this increase was suppressed by PAR-1 knockdown (Figs 4, 5, and 7).
  • GSK3/Sgg knockdown reduced SP/TP phosphorylation but did not reduce tau levels, did not prevent Aβ42-induced cytosolic tau increase or microtubule-bound tau decrease, and did not suppress Aβ42-enhanced tau toxicity (Figs 2 and 6).

Methods

  • Transgenic Drosophila expressing human 0N4R tau alone or with Aβ42, driven by gmr-GAL4 in the retina or elav-GAL4 pan-neuronally; RNAi knockdown or overexpression of PAR-1 and Sgg/GSK3; age-matched male flies used.
  • In vivo microtubule-binding assay: head lysates with taxol, centrifugation to separate cytosol supernatant and microtubule pellet, then western blotting with pan-tau and phospho-specific antibodies; phosphatase treatment and quantification by ImageJ/Odyssey.
  • Toxicity assessed by eye surface area and histology; statistics used Student’s t-test or one-way ANOVA with Tukey post hoc; typical n = 4–5 for blots and N = 6–8 for eye area.

Limitations

  • Stated: the authors cannot draw an explicit conclusion about which tau species, tauupper or taulower, is more toxic; mechanisms of tau-mediated neurodegeneration remain unclear; further studies in mammalian model systems are warranted.
  • Stated/evident: the Drosophila model does not form fibrils or detergent-insoluble aggregates, so findings may reflect toxicity of soluble, non-aggregated tau and early stages of tau mismetabolism rather than NFT formation.
  • Evident: conclusions rely on overexpression and RNAi in fly retina/neurons, with no human tissue or mammalian in vivo validation in this paper.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pgen.1005917

Cites

117 of 117 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

59 of 124 cited sources checked · 22 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    Aβ42 co-expression enhances tau-mediated retinal degeneration in fly eyes.

    “As reported previously, co-expression of Aβ42 in fly eyes using the pan-retinal driver gmr-Gal4 enhanced tau-mediated retinal degeneration ([58] and S1 Fig).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] K Iijima, 2010, Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease, Hum Mol Genet source
  • Premisecitation

    Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity.

    “Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity [26, 53–56].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [26] S Chatterjee, 2009, Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model, Hum Mol Genet source

      The Results sections on S2A tau identify Ser262/356 as PAR-1 phosphorylation sites and report that the phosphorylation-resistant mutant was less toxic than wild-type tau in the fly eye. The claim overstates the GSK3-target-site part: the Discussion reports substantial toxicity in tau resistant to GSK-3β/Shaggy phosphorylation, while the Results report relatively normal eyes despite elevated phosphorylation at GSK-3β-relevant epitopes. No page numbers are available in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [53] I Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source
    • cites [54] ML Steinhilb, 2007, S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila, J Neurosci Res source
    • cites [55] K Papanikolopoulou, 2015, Temporally distinct phosphorylations differentiate Tau-dependent learning deficits and premature mortality in Drosophila, Hum Mol Genet source
    • cites [56] TA Fulga, 2007, Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo, Nat Cell Biol source
  • Premisecitation

    Formation of fibrils or detergent-insoluble aggregates are not detected in the presence or absence of Aβ in Drosophila models.

    “Formation of fibrils or detergent-insoluble aggregates are not detected in the presence or absence of Aβ [58, 59]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [58] K Iijima, 2010, Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease, Hum Mol Genet source

      The Introduction (page unavailable) says neurofibrillary tangles are not observed in fly neurons. Figure 2D (page unavailable) reports that Aβ42 co-expression did not increase sarkosyl-insoluble tau, but it does not say detergent-insoluble tau was undetectable in either condition. The claim of no detectable fibrils or insoluble aggregates with or without Aβ is therefore stronger than the cited evidence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [59] CW Wittmann, 2001, Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles, Science source
  • Interpretationcitation

    Aβ42-mediated augmentation of tau toxicity is not simply due to an overall increase in the level of tau.

    “suggesting that Aβ42-mediated augmentation of tau toxicity is not simply due to an overall increase in the level of tau [58].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] K Iijima, 2010, Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease, Hum Mol Genet source
  • Premisecitation

    Studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity depends on tau phosphorylation at these sites.

    “Notably, studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity caused by Aβ depends on tau phosphorylation at these sites [39, 45, 56–58].”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci source

      The results section (page unavailable) reports increased tau phosphorylation at pS262/pS356 and pS202/pT205 in Aβ-exposed cultured hippocampal neurons. It does not report a transgenic Drosophila experiment or establish that phosphorylation at those sites is required for Aβ-induced augmentation of tau toxicity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [45] W Yu, 2012, A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses and dendritic spines, Hum Mol Genet source

      In 'Expression of non-phosphorylatable form of tau blocks Aβ toxicity' (page not available), Aβ increased tau phosphorylation at the 12E8 sites in cultured rat hippocampal neurons, and non-phosphorylatable tau ameliorated Aβ-induced spine and synaptic-marker loss. The Introduction and 'Expression of a non-phosphorylatable form of tau blocks PAR-1/MARK toxicity' describe Drosophila evidence that PAR-1-site phosphorylation is required for tau toxicity, but do not show Aβ-induced augmentation of tau toxicity in transgenic Drosophila. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [56] TA Fulga, 2007, Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo, Nat Cell Biol source
    • cites [57] G Mairet-Coello, 2013, The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Abeta oligomers through Tau phosphorylation, Neuron source
    • cites [58] K Iijima, 2010, Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease, Hum Mol Genet source

      The Results and Discussion report that the non-phosphorylatable Ser262Ala mutation prevented Aβ42-associated neurodegeneration in transgenic Drosophila. The paper does not establish the same dependence in cultured neurons, or show that phosphorylation at the other sites measured is required for the effect. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 26
  • The quote only partly states this claim. 1

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

    Premisecitation

    GSK3 is a proline-directed kinase that contributes to phosphorylation of tau at SP/TP sites.

    “GSK3 is a proline-directed kinase that contributes to phosphorylation of tau at serine or threonine followed by proline (i.e., SP/TP sites) [46–49]”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [46] F Hernandez, 2010, GSK3: a possible link between beta amyloid peptide and tau protein, Exp Neurol source
    • cites [47] K Ishiguro, 1993, Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments, FEBS Lett source

      The Results identify GSK3β as TPKI and report that TPKI phosphorylates tau at specific serine and threonine residues, supporting its role in tau phosphorylation. The passages do not identify those residues as SP/TP sites or describe GSK3β as proline-directed, so that specificity is not established by our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [48] BR Sperber, 1995, Glycogen synthase kinase-3 beta phosphorylates tau protein at multiple sites in intact cells, Neurosci Lett source

      The Results report increased tau phosphorylation at several serine and threonine sites in cells expressing GSK3β. The introduction says GSK3α has been suggested to act as a proline-directed threonine kinase, but says GSK3β’s site specificity was not fully elucidated. The paper therefore supports GSK3β’s contribution to tau phosphorylation, but does not establish the claimed SP/TP specificity for GSK3β. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [49] DP Hanger, 2007, Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis, J Biol Chem source

  • May combine two claims.

    Premisecitation

    In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK.

    “In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
    Quote in the paperSubstantial claim4 of 10 sources checked
    • cites [2] M Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
    • cites [35] J Busciglio, 1995, beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding, Neuron source
    • cites [36] A Ferreira, 1997, Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta, Mol Cell Neurosci source
    • cites [37] A Takashima, 1998, Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons, Neurosci Res source
    • cites [38] QL Ma, 2009, Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin, J Neurosci source

      Figure 5 reports increased tau Ser422 phosphorylation after Aβ oligomer treatment in cultured neurons, and the Discussion reports increased phosphorylated tau in a 3xTg-AD mouse model under a high-fat diet. The Discussion says GSK3β is known to be activated by Aβ, but predicts rather than demonstrates its activation through the mechanism studied here. The cited passages do not establish that Aβ co-expression increases active GSK3 and PAR-1/MARK; PAR-1/MARK is not reported. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci source

      In “Synapses disappear in regions of Tau missorting” (page unavailable), the paper reports increased Tau phosphorylation and strong local activation of MARK after Aβ-oligomer treatment. It explicitly says GSK3β activity remained unchanged. The experiments described used treated cultured neurons, not co-expression of Aβ in both cellular and animal models. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [40] FG De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging source

      Results §3.3 reports increased tau phosphorylation at Thr231 and Ser404 after Aβ-oligomer exposure in cultured rat hippocampal neurons. The Introduction also reports prior findings of GSK-3β activation and describes transgenic mice expressing APP and tau. However, this paper does not show that Aβ co-expression increases active GSK3 in its models, and the cited passages do not establish an increase in active PAR-1/MARK. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [41] J Folwell, 2010, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp Neurol source
    • cites [43] QL Ma, 2006, Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro, J Neurosci Res source
    • cites [44] O Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet source

      The Discussion reports that Aβ42 increased tau phosphorylation in earlier cell and mouse studies, and that Arctic Aβ42 increased GSK-3 activity in this paper's flies. But the Results found no increase in phosphorylation at the tested Ser262 and Ser356 tau sites in those flies; the paper identifies these as MARK substrates without reporting increased PAR-1/MARK activity. The citation therefore supports only part of the combined claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases.

    “Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases [41, 44, 53, 59–63].”
    Quote in the paperSubstantial claim4 of 8 sources checked
    • cites [41] J Folwell, 2010, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp Neurol source
    • cites [44] O Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet source

      The Introduction describes human-tau fly models with neuronal dysfunction and reports that co-expression with Shaggy, a conserved GSK-3 homologue, worsens neurotoxic phenotypes. It does not establish progressive neurodegeneration or show that conserved kinases phosphorylate human tau at AD-related sites in those models. The Results examine phosphorylation sites on endogenous fly tau instead and find no change at the Ser262 or Ser356 homologous epitopes under the conditions tested. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [53] I Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source
    • cites [59] CW Wittmann, 2001, Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles, Science source
    • cites [60] A Mudher, 2004, GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila, Mol Psychiatry source
    • cites [61] GR Jackson, 2002, Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila, Neuron source
    • cites [62] S Grammenoudi, 2006, Cell type-specific processing of human Tau proteins in Drosophila, FEBS Lett source
    • cites [63] K Iijima-Ando, 2012, Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1, PLoS Genet source

  • May combine two claims.

    Premisecitation

    The neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau.

    “suggesting that the neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau [11–14].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [11] CM Cowan, 2013, Are tau aggregates toxic or protective in tauopathies?, Frontiers in neurology source
    • cites [12] N Sahara, 2008, Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration, Curr Alzheimer Res source
    • cites [13] KV Kuchibhotla, 2014, Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo, Proc Natl Acad Sci U S A source
    • cites [14] K Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD.

    “Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”
    Quote in the paperSubstantial claim3 of 8 sources checked
    • cites [2] M Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
    • cites [35] J Busciglio, 1995, beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding, Neuron source
    • cites [36] A Ferreira, 1997, Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta, Mol Cell Neurosci source
    • cites [37] A Takashima, 1998, Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons, Neurosci Res source
    • cites [38] QL Ma, 2009, Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin, J Neurosci source

      The Results section on cultured hippocampal neurons (page unavailable) reports that Aβ42 oligomers significantly increased tau phosphorylation at Ser422, a site the paper associates with AD neurodegeneration. The paper also reports increased tau Ser422 phosphorylation in 3xTg-AD mice on a high-fat diet, but it does not establish that Aβ itself caused that increase in vivo. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci source

      The Abstract and Figure 5 passage report that Aβ oligomers increased tau phosphorylation at AD-associated epitopes, including 12E8 and AT8, in cultured hippocampal neurons. The paper’s experimental model was in vitro; it does not establish the claimed effect in an in vivo model. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [40] FG De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging source

      The Results (§3.3; page unavailable) show that Aβ oligomers increased phosphorylation at the AD-associated Thr231 and Ser404 sites in cultured neurons. The Introduction (§1; page unavailable) reports tau hyperphosphorylation after Aβ injection in animals, but does not establish phosphorylation at those specific sites in vivo; this paper's own experiments were in vitro. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [41] J Folwell, 2010, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp Neurol source

  • May combine two claims.

    Premisecitation

    Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis that lies upstream of tau-induced neurodegeneration.

    “Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”
    Quote in the paperSubstantial claim2 of 9 sources checked
    • cites [2] M Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
    • cites [3] J Lewis, 2001, Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP, Science source
    • cites [4] J Gotz, 2001, Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils, Science source
    • cites [5] S Oddo, 2004, Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome, Neuron source
    • cites [6] DJ Selkoe, 2011, Resolving controversies on the path to Alzheimer's therapeutics, Nat Med source
    • cites [7] ED Roberson, 2007, Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model, Science source
    • cites [8] TL Spires-Jones, 2014, The intersection of amyloid beta and tau at synapses in Alzheimer's disease, Neuron source
    • cites [9] A Caccamo, 2005, Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders, Neurobiol Aging source
    • cites [10] MA Chabrier, 2012, Soluble abeta promotes wild-type tau pathology in vivo, J Neurosci source

  • Classified as probably not a substantial claim.

    Premisecitation

    Activities of GSK3 and PAR-1/MARKs are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity.

    “the activities of two major tau kinases, GSK3 and PAR-1/microtubule affinity-regulating kinases (MARKs), are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity [37, 39, 43–45].”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [37] A Takashima, 1998, Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons, Neurosci Res source
    • cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci source

      In the Discussion and Figure 6, the paper links Aβ-induced MARK/Par-1 activity to tau detachment from microtubules and microtubule destabilization. It does not support the same association for GSK3β in this experiment: the Discussion says GSK3β activity did not increase in dendrites with missorted tau. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [43] QL Ma, 2006, Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro, J Neurosci Res source
    • cites [44] O Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet source

      The Introduction links Aβ to increased tau phosphorylation and GSK-3 activation; the Discussion identifies MARK as a kinase that phosphorylates tau. But the paper does not establish that either kinase causes tau to detach from microtubules or that PAR-1/MARK augments Aβ-induced tau toxicity. In its fly model, the Discussion reports no observable change in overall tau phosphorylation with Aβ42 expression. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [45] W Yu, 2012, A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses and dendritic spines, Hum Mol Genet source

      The Introduction and the section ‘Expression of non-phosphorylatable form of tau blocks Aβ toxicity’ link PAR-1/MARK-mediated tau phosphorylation to tau toxicity and Aβ-induced synaptic and spine damage (page numbers unavailable). Our copy does not establish the corresponding role for GSK3 or state that either kinase causes tau to detach from microtubules. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In Drosophila, tau phosphorylation at SP/TP sites decreases tau binding to microtubules, whereas replacing these sites with unphosphorylatable Ala significantly increases binding.

    “In Drosophila, tau phosphorylation at proline-directed Ser and Thr (SP/TP) sites decreases tau binding to microtubules, whereas replacing these phosphorylation sites with unphosphorylatable Ala significantly increases binding [25, 26].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [25] S Feuillette, 2010, Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein, J Neurochem source
    • cites [26] S Chatterjee, 2009, Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model, Hum Mol Genet source

  • May combine two claims.

    Premisecitation

    Aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system.

    “The majority of tau species (including tau lacking phosphorylation at Ser262/356) are degraded by the proteasome [20], while aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system [79–84].”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [79] CA Dickey, 2006, HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites, FASEB J source
    • cites [80] Y Wang, 2010, Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation, Autophagy source

      The paper’s discussion of tau degradation (page unavailable) says aggregated tau is removed by macroautophagy and tau phosphorylated at KXGS motifs in the repeat domains can be degraded by the autophagy-lysosomal system. Our copy does not identify Ser262/356 specifically, so it does not establish that site-specific part of the claim. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [81] PJ Dolan, 2011, Decreases in valosin-containing protein result in increased levels of tau phosphorylated at Ser262/356, FEBS Lett source

      The Discussion states that tau phosphorylated at KXGS motifs is degraded by autophagy rather than the proteasome, and §3.4 reports increased soluble Ser262/356-phosphorylated tau after autophagy inhibition. These passages support the phosphorylated-tau part of the claim, but our copy does not establish that aggregated tau is degraded by the autophagy-lysosome system; the study reports no change in insoluble tau after VCP knockdown. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [82] T Hamano, 2008, Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression, Eur J Neurosci source
    • cites [83] Z Berger, 2006, Rapamycin alleviates toxicity of different aggregate-prone proteins, Human Molecular Genetics source

      In “Rapamycin enhances clearance of tau and decreases tau toxicity in vivo” (pp. 4–5), rapamycin reduced aggregate-prone or insoluble tau, and blocking autophagy abolished its effect on insoluble tau. The paper does not identify phosphorylation at Ser262/356, and it says mutant tau can be degraded by autophagy when induced but is not predominantly degraded that way under basal conditions. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [84] C Jo, 2014, Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52, Nature communications source

      The Results ('Autophagy mediates the degradation of phosphorylated tau'; page unavailable) show that blocking autophagy or lysosomal function attenuated phosphorylated-tau degradation. The Discussion reports reduced Ser262/356-phosphorylated tau after Nrf2 activation or NDP52 overexpression. The Results ('NDP52 decreases sarkosyl-insoluble tau in AD cases'; page unavailable) link NDP52 to less insoluble tau, but suggest prevention of aggregation through phosphorylated-tau clearance rather than demonstrating degradation of already aggregated tau. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The autophagic system and endosome/lysosome pathways are compromised in AD brains.

    “Consistent with this, the autophagic system and endosome/lysosome pathways are compromised in AD brains, and chronic disturbance of this system is thought to contribute to protein accumulation and neurodegeneration [85–87].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [85] RA Nixon, 2007, Autophagy, amyloidogenesis and Alzheimer disease, J Cell Sci source
    • cites [86] K Inoue, 2012, Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway, Mol Neurodegener source

      The Background reports macroautophagy defects in brain sections from patients with AD and discusses disruption of the macroautophagy–lysosomal pathway. It also presents defective protein degradation as a possible contributor to pathological inclusions. The cited passages do not establish that the endosomal pathway is compromised in AD brains. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [87] K Moreau, 2014, PICALM modulates autophagy activity and tau accumulation, Nature communications source

      The paper’s introductory discussion (page not available) describes excess autophagosomes in affected AD neurons and suggests defects in their removal. Its Discussion links altered autophagy to tau accumulation and possible neurodegeneration. It does not establish that endosome/lysosome pathways themselves are compromised in AD brains; its evidence about those pathways concerns how CALM regulates autophagy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Drosophila PAR-1 kinase is a functional homolog of MARKs and is the major kinase of human tau at Ser262 and Ser356 expressed in fly eye and brain.

    “Drosophila PAR-1 kinase, a functional homolog of MARKs, is the major kinase of human tau at Ser262 and Ser356 expressed in fly eye and brain [53, 63]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [53] I Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source
    • cites [63] K Iijima-Ando, 2012, Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1, PLoS Genet source

      The Results section on PAR-1 and Ser262 identifies MARK as the mammalian homolog of Drosophila PAR-1 and says PAR-1 knockdown reduces tau phosphorylation at Ser262, suggesting it is the major Ser262 kinase in the fly eye. The paper does not establish that PAR-1 is the major kinase at Ser356 or that this major-kinase finding applies to the fly brain. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity.

    “In contrast to PAR-1/MARK, blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Tau proteins expressed in fly retina are detected as two major bands by western blotting with pan-tau antibody.

    “Tau proteins expressed in the fly retina are detected as two major bands by western blotting with pan-tau antibody (Fig 1B).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    TAU-1 antibody detects taulower.

    “Western blotting with TAU-1 antibody, which specifically recognizes tau protein without phosphorylation at several AD-related sites (Ser194, Ser195, Ser198, and Ser202), detected taulower (Fig 1C, TAU-1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ42 increases the level of tau in the cytosol fraction and decreases the level in the microtubule fraction in fly retina co-expressing tau and Aβ42.

    “We found that the levels of tau in the cytosol fraction were significantly elevated, whereas the levels in the microtubule fraction were reduced, in the fly retina co-expressing Aβ42 and tau (Fig 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231.

    “blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Co-expression of Aβ42 did not significantly change levels of tubulin in the form of microtubules or levels of acetylated or tyrosinated tubulin.

    “co-expression of Aβ42 did not significantly change the levels of tubulin in the form of microtubules (Fig 1B, tubulin) or the levels of acetylated or tyrosinated tubulin (S4 Fig)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The effects of Aβ42 on S2A tauupper were smaller than those on wild-type tau: Aβ42 caused a 3-fold increase in wild-type tauupper in the cytosol, but only a 1.6-fold increase in S2A tauupper.

    “the effects were smaller than those in wild-type tau: Aβ42 caused a 3-fold increase in the level of wild-type tauupper in the cytosol (Fig 1B), but only a 1.6-fold increase in the level of S2A tauupper (Fig 3F, right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Knockdown of Sgg significantly decreases phosphorylation levels of tau at SP/TP sites and shifts all tau species to lower-molecular weight regions.

    “knockdown of Sgg significantly decreased phosphorylation levels of tau at SP/TP sites and shifted all tau species to lower–molecular weight regions (Fig 2)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PAR-1 knockdown reduces tau levels in the presence of Aβ42, with a more prominent reduction in taulower than tauupper.

    “PAR-1 knockdown reduced the levels of tau (Fig 5C, tauC/Tau46), and the reductions in the levels of taulower were more prominent than those of tauupper (Fig 5C, tauC/Tau46,).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ42 still increased the level of S2A tauupper in the cytosol and decreased that in the microtubule fraction.

    “although Aβ42 still increased the level of S2A tauupper in the cytosol and decreased that in the microtubule fraction (Fig 3F)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In GSK3/Sgg knockdown background, co-expression of Aβ42 was still capable of increasing level of tau in cytosolic fraction and decreasing level in microtubule fraction.

    “In vivo microtubule-binding assays revealed that, in the GSK3/Sgg knockdown background, co-expression of Aβ42 was still capable of increasing the level of tau in the cytosolic fraction and decreasing the level in the microtubule fraction (Fig 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expression of neither Aβ42 alone nor Aβ42 with GSK3β/Sgg RNAi caused a reduction in eye size.

    “Under this experimental condition, expression of neither Aβ42 alone nor Aβ42 with GSK3β/Sgg RNAi caused a reduction in eye size (S6 Fig)”
    Quote in the paperSubstantial claim

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

    Findingown data

    The SDS-PAGE migration pattern of S2A tau differed from that of wild-type tau.

    “Moreover, the SDS-PAGE migration pattern of S2A tau differed from that of wild-type tau.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When phosphorylation levels of S2A tau at Ser202 were normalized against total levels of S2A tau, they were not elevated; instead, they were reduced relative to wild-type tau.

    “when the phosphorylation levels of S2A tau at Ser202 were normalized against total levels of S2A tau, they were not elevated; instead, they were reduced relative to those of wild-type tau (Fig 3B and 3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PAR-1/MARKs are non-SP/TP kinases that phosphorylate tau at Ser262 and Ser356 in the repeat domains located in the microtubule-binding region.

    “whereas PAR-1/MARKs are non-SP/TP kinases that phosphorylate tau at Ser262 and Ser356 in the repeat domains located in the microtubule-binding region [50].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] G Drewes, 1997, MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption, Cell source

  • May combine two claims.

    Interpretationown data

    The Aβ42-induced increase in cytosolic tau and decrease in microtubule-bound tau occurs regardless of tau phosphorylation status.

    “These results suggest that, regardless of its phosphorylation status, microtubule-unbound free tau in the cytosol is more abundant in the presence of Aβ42.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The roles of, and interdependency between, tau phosphorylation by GSK3 and MARK/PAR-1 in an early step of tau mismetabolism, such as tau mislocalization and stabilization of mislocalized tau, are not fully understood.

    “However, the roles of, and interdependency between, tau phosphorylation by GSK3 and MARK/PAR-1 in an early step of tau mismetabolism, such as tau mislocalization and stabilization of mislocalized tau, are not fully understood.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The difference between the original taulower and tauupper species includes not only phosphorylation status at GSK3-target sites but also additional post-transcriptional modifications and/or differences in cellular localization.

    “These results raise the possibility that the difference between the original taulower and tauupper species includes not only phosphorylation status at GSK3-target sites but also additional post-transcriptional modifications and/or differences in cellular localization.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    One membrane was probed with anti-tubulin and used as the loading control for other blots in each experiment.

    “One of the membranes was probed with anti-tubulin, and used as the loading control for other blots in each experiment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All experiments were performed using age-matched male flies.

    “All experiments were performed using age-matched male flies, and genotypes are described in S1 Table.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    S2A mutation preferentially reduces the levels of taulower, and partially suppresses the Aβ42-mediated increase in the levels of tau mislocalized from the microtubule to the cytosol.

    “Taken together, these data demonstrate that S2A mutation preferentially reduces the levels of taulower, and partially suppresses the Aβ42-mediated increase in the levels of tau mislocalized from the microtubule to the cytosol.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in the levels of tau species measured by western blotting reflect changes in tau protein stability.
    • Rests on an assumption: The S2A mutation (Ser262/356 to Ala) does not alter tau properties other than preventing phosphorylation at these sites.

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

    Study design and conductnone given

    Western blots were repeated a minimum of three times with different animals.

    “Western blots were repeated a minimum of three times with different animals and representative blots are shown.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    Blocking tau phosphorylation at GSK3/Sgg sites is not sufficient to reduce tau levels, suppress mislocalization of tau to the cytosol, or diminish Aβ42-induced augmentation of tau toxicity.

    “Taken together, these results suggest that blocking tau phosphorylation at GSK3/Sgg sites is not sufficient to suppress either mislocalization of tau to the cytosol or Aβ42-induced augmentation of tau toxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This study highlights critical roles of tau phosphorylation at Ser262/356 in stabilization of tau and its contribution to tau-mediated neurodegeneration.

    “This study highlights the critical roles of tau phosphorylation at Ser262/356 in stabilization of tau and its contribution to tau-mediated neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tau phosphorylation at Ser262 and Ser356 stabilizes less phosphorylated forms of tau (taulower) but does not promote tau phosphorylation at SP/TP sites.

    “These results suggest that tau phosphorylation at Ser262 and Ser356 stabilizes less phosphorylated forms of tau (taulower) but does not promote tau phosphorylation at SP/TP sites (see also Fig 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in the levels of tau species measured by western blotting reflect changes in tau protein stability.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Targeting multiple pools of abnormal tau stabilized by distinct pathways could additively suppress tau-mediated toxicity.

    “Thus, targeting multiple pools of abnormal tau stabilized by distinct pathways could additively suppress tau-mediated toxicity.”
    Quote in the paperNot a substantial claim
37 of 37

  • The paper relies on this without support.

    Changes in the levels of tau species measured by western blotting reflect changes in tau protein stability.

    “These results suggest that tau phosphorylation at Ser262 and Ser356 stabilizes less phosphorylated forms of tau (taulower) but does not promote tau phosphorylation at SP/TP sites (see also Fig 4).”

  • The paper relies on this without support.

    The S2A mutation (Ser262/356 to Ala) does not alter tau properties other than preventing phosphorylation at these sites.

    “These mutations abolished tau phosphorylation at Ser262 (Fig 3B, pSer262).”

  • The paper relies on this without support.

    Changes in tau protein levels reflect changes in tau stability rather than synthesis or other processes.

    “Taken together, these results indicate that PAR-1 stabilizes less phosphorylated forms of tau (taulower) through phosphorylation at Ser262 and Ser356.”

  • The paper relies on this without support.

    Aβ42-induced tau toxicity in the Drosophila retina is relevant to AD pathogenesis.

    “suggesting the relevance of this step to AD pathogenesis.”

  • The paper relies on this without support.

    The TAU-1 antibody specifically recognizes tau lacking phosphorylation at Ser202.

    “western blot analysis using the TAU-1 antibody, which specifically recognizes tau lacking phosphorylation at Ser202, revealed that blocking tau phosphorylation at Ser262/356 by either by PAR-1 knockdown (Fig 5D) or introduction of the S2A mutation (Fig 3B), did not increase, but rather significantly decreased, the levels of tau species that are not phosphorylated at Ser202.”
5 of 5

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.

  • Fly sex differs between the general methods and histological analysis

    Major

    The fly-stock methods state that all experiments used male flies, but the histological-analysis methods specify female flies.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M.
Affiliations
  • Thomas Jefferson University (US)
  • National Center for Geriatrics and Gerontology (JP)
Corresponding author
  • Ando, Kanae
  • Iijima, Koichi M.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2016-03-29
Volume
12
Issue
3
Pages
e1005917
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1005917
PMC
PMC4811436
OpenAlex
W2325575548
Cited by
105
References
117
Citations by year
2026: 5 · 2025: 11 · 2024: 11 · 2023: 7 · 2022: 13 · 2021: 5 · 2020: 16 · 2019: 10 · 2018: 10 · 2017: 10 · 2016: 7
FWCI
9.93
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Medicine Forum (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Alzheimer's Association (NIRG-08-91985)
  • Hoansha Foundation
  • National Center for Geriatrics and Gerontology
  • Tokyo Metropolitan University
  • National Institutes of Health
  • Japan Society for the Promotion of Science (15K06712, 15H01564)
  • National Institute on Aging (U01AG046170, R01AG032279)
  • National Institute of General Medical Sciences (R01GM084947, GM084947)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tau phosphorylation, amyloid-beta 42, Alzheimer's disease, glycogen synthase kinase-3, tau toxicity, neurodegeneration, Drosophila model
MeSH terms
Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Disease Models, Animal, Drosophila, Hippocampus, Humans, Microtubules, Neurons, Phosphorylation, Tubulin, Amyloid beta-Peptides, tau Proteins, Animals, Genetically Modified, Glycogen Synthase Kinase 3, Receptor, PAR-1

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 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review