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Cited by 12Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyAmyotrophic Lateral Sclerosis Research

The DOI matches its Crossref record; 133 of the 133 references it cites were found in a registry or an index; 22 of the 176 sources its claims cite were checked for support.

GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau

Open access
Acosta Ingram, Diana, Turkes, Emir, Kim, Tae Yeon, Vo, Sheeny, Sweeney, Nicholas, Bonte, Marie-Amandine, Rutherford, Ryan, Julian, Dominic L., Pan, Meixia, Marsh, Jacob, Argouarch, Andrea R., Wu, Min, Scharre, Douglas W., Bell, Erica H., Honig, Lawrence S., Vonsattel, Jean Paul, Serrano, Geidy E., Beach, Thomas G., Karch, Celeste M., Kao, Aimee W., Hester, Mark E., Han, Xianlin, Fu, Hongjun·2025·Nature Communications
DOI 10.1038/s41467-025-58585-wPMC PMC11982250
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Abstract

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux. Modulating GRAMD1B in iPSC-derived neurons also alters key autophagy-related components such as PI3K, phospho-AKT, and p62, as well as phosphorylated tau, and CDK5R1. Blocking GRAMD1B function decreases free cholesterol and lipid droplets. Knocking down GRAMD1B additionally reduces phosphorylated tau, and CDK5R1 expression. Our findings elucidate the role of GRAMD1B in the nervous system and highlight its relevance to FTLD and AD. The relationship between lipid dyshomeostasis and tau pathology in FTLD and AD remains unclear. Here, the authors demonstrate that GRAMD1B contributes to lipid dyshomeostasis, autophagy impairment, and tau hyperphosphorylation in neurons.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

GRAMD1B, a nonvesicular cholesterol transporter, is increased in MAPT R406W human neural organoids, human FTLD/AD brain tissue, and PS19 tau mice. Modulating GRAMD1B alters free cholesterol, lipid droplets, autophagic flux, and phosphorylated tau, and inhibiting it with AI-3d or knocking it down reverses several of these phenotypes.

Key findings

  • In MAPT R406W human neural organoids, GRAMD1B was increased in excitatory neurons by scRNA-seq and validated by RNAscope; D120 heterozygous organoids showed increased GRAMD1B protein (P = 0.0172), increased filipin/free cholesterol (P = 0.0070), increased lipid droplets (P = 0.0005), decreased HMGCS1 (P = 0.0102), and unchanged SREBP2 (P = 0.1493).
  • Human FTLD cases showed increased global GRAMD1B, filipin, and Oil-Red-O versus controls (P = 0.0286 each); GRAMD1B correlated with PHF1 in FTLD (r = 0.9136, p < 0.01) and AD (r = 0.7386, p < 0.05), while single PHF1+ cells had lower GRAMD1B, filipin, and lipid droplets, with negative correlations (e.g., PHF1 vs GRAMD1B r = −0.6479, p < 0.0001).
  • GRAMD1B overexpression increased free cholesterol, lipid droplets, PI3K, phospho-AKT, p62 puncta, 12E8 tau phosphorylation, and CDK5R1; GRAMD1B shRNA knockdown decreased these readouts. In the FUW-mCherry-GFP-LC3 autophagy reporter, overexpression increased yellow puncta and p62 puncta, while knockdown reduced them; the red/yellow puncta ratio decreased with overexpression (P = 0.0081) and increased with knockdown (P = 0.0002).
  • The Aster inhibitor AI-3d reduced filipin, lipid droplets, PI3K, phospho-AKT, p62, 12E8, and CDK5R1 in WT and MAPT R406W heterozygous organoids, without significantly changing excitatory neuron proportions.

Methods

  • The study used hiPSC-derived human neural organoids with CRISPR-Cas9 isogenic control, MAPT R406W heterozygous, and homozygous lines; scRNA-seq at D72 and D120; IF, WB, RNAscope HiPlex smFISH, lipidomics of conditioned medium, microelectrode array recordings, human post-mortem entorhinal cortex from FTLD/AD and controls, PS19 tau mice, primary mixed neurons/astrocytes, N2a cells, and iPSC-derived neurons.
  • Interventions included lentiviral GRAMD1B overexpression and shRNA knockdown, the FUW-mCherry-GFP-LC3 autophagy reporter with bafilomycin A1, and AI-3d treatment. Analyses included pseudobulked differential expression, gene-set enrichment, Pearson correlations, t tests, Mann-Whitney tests, and ANOVA, with significance at P < 0.05.
  • scRNA-seq analysis included 44,697 single cells across two timepoints and three genotypes; lipidomics analyzed 16 samples (n = 4 replicates per group at Day 60 and Day 120).

Limitations

  • The paper states that AI-3d inhibits all Aster proteins, including GRAMD1A, GRAMD1B, and GRAMD1C, so a GRAMD1B-specific inhibitor is still needed; it also states that the organoid cultures lack microglia, a vascular system, and mature oligodendrocytes, and that unguided organoid culture may introduce variability, stress, and cell death.
  • The paper states that its organoids predominantly express 3R-tau rather than 4R-tau, lack an aging phenotype, and that limited hiPSC availability led to use of the same gender and a different patient line for the homozygous MAPT R406W line, leaving sex-dependent effects unaddressed.
  • The paper states that MEA recordings lack spatial resolution, have limited time-course data, and measure channel-level local field potentials rather than single-unit activity; evident from the text, human post-mortem correlation analyses used small case numbers (n = 4 control and n = 4 FTLD), and WB of whole organoid lysate may mask neuronal PHF1 changes, as the authors note for homozygous organoids.

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

Integrity signals

Registry

Crossref · 10.1038/s41467-025-58585-w

Cites

133 of 133 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

22 of 176 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    GRAMD1B is a nonvesicular cholesterol transporter (Aster protein).

    “GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter”
    • Also stated in: § Introduction · plain
      “Aster proteins encoded by GRAMD1A, GRAMD1B, and GRAMD1C) play a role in the rapid and selective delivery of lipids via nonvesicular transport in response to high cell membrane cholesterol39.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [39] Ercan, B., Naito, T., Koh, D. H. Z., Dharmawan, D. & Saheki, Y. Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b. EMBO J. 40, e106524 (2021). source
    • cites [40] Sandhu, J. et al. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell 175, 514–529 (2018). source
    • cites [41] Ferrari, A. et al. Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake. Science 382, eadf0966 (2023). source
  • Findingown data

    Overexpression of GRAMD1B increases lipid droplets in HNOs.

    “overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux.”
    • Also stated in: § Increased expression of GRAMD1B in HNOs can recapitulate lipid changes and changes in cholesterol synthesis proteins observed in mutant heterozygous HNOs · plain
      “We found GRAMD1B overexpression can increase free cholesterol and lipid droplets (Supplementary Fig. 5a, b).”
    Quote in the paperSubstantial claim
  • Findingown data

    GRAMD1B is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation.

    “We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation.”
    • Also stated in: § Mutant HNOs show dysregulated pathways associated with lipid homeostasis in excitatory neurons as revealed by scRNA-seq analysis · plain
      “Our studies revealed increased GRAMD1B expression in mutant HNOs”
    • Also stated in: § Mutant HNOs show dysregulated pathways associated with lipid homeostasis in excitatory neurons as revealed by scRNA-seq analysis · plain
      “RNAscope smFISH validated the increased expression of GRAMD1B, VEGFB, and NR2F2 in mutant MAPT R406W HNOs compared to isogenic controls.”
    Quote in the paperSubstantial claim
  • Findingown data

    Overexpression of GRAMD1B increases free cholesterol in HNOs.

    “overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux.”
    • Also stated in: § Increased expression of GRAMD1B in HNOs can recapitulate lipid changes and changes in cholesterol synthesis proteins observed in mutant heterozygous HNOs · plain
      “We found GRAMD1B overexpression can increase free cholesterol and lipid droplets (Supplementary Fig. 5a, b).”
    Quote in the paperSubstantial claim
  • Findingown data

    D120 HNOs exhibit primarily 3 R Tau by qRT-PCR.

    “qRT-PCR also reveals D120 HNOs exhibit primarily 3 R Tau (Supplementary Fig. 1a, b).”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim. 88
  • It may state two separate claims as one. 71
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Aster proteins, such as GRAMD1B, act at contact sites formed between the endoplasmic reticulum and the plasma membrane without membrane fusion.

    “Aster proteins, such as GRAMD1B, act at contact sites formed between the endoplasmic reticulum and the plasma membrane without membrane fusion40,41.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [40] Sandhu, J. et al. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell 175, 514–529 (2018). source
    • cites [41] Ferrari, A. et al. Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake. Science 382, eadf0966 (2023). source

  • It may state two separate claims as one.

    Interpretationcitation

    The lower level of PHF1 in homozygous HNOs may be due to increased inhibitory neuronal populations, which are less vulnerable to phosphorylated tau accumulation.

    “The lower level of PHF1 in homozygous HNOs may be due to increased inhibitory neuronal populations (Fig. 1e and f), which are less vulnerable to phosphorylated tau accumulation31,50.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [31] Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019). source
    • cites [50] Leng, K. et al. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat. Neurosci. 24, 276–287 (2021). source

  • Probably not a substantial claim.

    Premisecitation

    Aster proteins encoded by GRAMD1A, GRAMD1B, and GRAMD1C play a role in rapid and selective delivery of lipids via nonvesicular transport in response to high cell membrane cholesterol.

    “Importantly, an evolutionarily conserved family of lipid transfer proteins (e.g., Aster proteins encoded by GRAMD1A, GRAMD1B, and GRAMD1C) play a role in the rapid and selective delivery of lipids via nonvesicular transport in response to high cell membrane cholesterol39.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Ercan, B., Naito, T., Koh, D. H. Z., Dharmawan, D. & Saheki, Y. Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b. EMBO J. 40, e106524 (2021). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationcitation

    The lack of 4 R isoforms of tau is a common disadvantage of most current culture methods of HNOs, which requires validation of findings in HNOs with both 4 R and 3 R tau, tau mouse models, or human postmortem brain tissue with tau pathology.

    “The lack of 4 R isoforms of tau is a common disadvantage of most current culture methods of HNOs5, which requires the validation of findings in HNOs with both 4 R and 3 R tau, tau mouse models, or human postmortem brain tissue with tau pathology52,53.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [5] Bowles, K. R. et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell 184, 4547–4563 (2021). 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 [52] Schoch, K. M. et al. Increased 4R-tau induces pathological changes in a human-tau mouse model. Neuron 90, 941–947 (2016). 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 [53] Parra Bravo, C. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187, 2446–2464.e22 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    This is consistent with previous reports of decreased neuronal activity in tau mouse models and in vitro models with tau pathology.

    “This is consistent with previous reports of decreased neuronal activity in tau mouse models and in vitro models with tau pathology53,54.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [53] Parra Bravo, C. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187, 2446–2464.e22 (2024). source
    • cites [54] Sohn, P. D. et al. Pathogenic tau impairs axon initial segment plasticity and excitability homeostasis. Neuron 104, 458–470 (2019). source

      The Results section reports a lower network burst rate in cultured tauV337M neurons, supporting one measure of decreased activity. But it also reports no significant difference in firing rate and more spikes per network burst; the Introduction describes increased, not decreased, network excitability in tau mouse models. The source therefore does not support the broad claim of decreased neuronal activity across both models. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    HNOs generated from hiPSCs of patients with MAPT mutations provide a complex in vitro model that exhibits transcriptional changes relevant to neurodegeneration.

    “Human neural organoids (HNOs) generated from human induced pluripotent stem cells (hiPSCs) of patients with MAPT mutations provide a complex in vitro model which also exhibits transcriptional changes that are relevant to neurodegeneration4,5.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [4] Glasauer, S. M. K. et al. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Rep. 17, 2127–2140 (2022). source
    • cites [5] Bowles, K. R. et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell 184, 4547–4563 (2021). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Previous studies suggest cholesterol changes may alter autophagy.

    “which is consistent with previous studies suggesting cholesterol changes may alter autophagy73.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [73] Barbero-Camps, E. et al. Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion. Autophagy 14, 1129–1154 (2018). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    CE accumulation could be due to the dyshomeostasis of lipid transport and/or the dysfunction of autophagy to degrade CE.

    “CE accumulation could be due to the dyshomeostasis of lipid transport35,36 and/or the dysfunction of autophagy to degrade CE37,38.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [35] Yin, F. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. 290, 1420–1453 (2022). source

      The cholesterol-and-cholesteryl-esters section reports elevated CE levels in AD brains, while the lipid-homeostasis section says disrupted lipid transport contributes to lipid dyshomeostasis. The source does not specifically connect impaired transport to CE accumulation. The autophagy clause has separate citations in the citing sentence and is not assessed against this source. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [36] Chew, H., Solomon, V. A. & Fonteh, A. N. Involvement of lipids in Alzheimer’s disease pathology and potential therapies. Front. Physiol. 11, 598 (2020). source

      The genetic-evidence table identifies cholesterol-transport and efflux pathways, and the Cholesterol Metabolism section discusses altered cholesterol homeostasis in AD. Neither passage says that disrupted transport causes cholesteryl ester (CE) accumulation, and the passages found do not link impaired autophagic degradation of CE to that accumulation. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [37] Li, L. et al. Lipids and membrane-associated proteins in autophagy. Protein Cell 12, 520–544 (2021). source
    • cites [38] Dong, H. & Czaja, M. J. Regulation of lipid droplets by autophagy. Trends Endocrinol. Metab. 22, 234–240 (2011). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Findings in iPSC-derived neurons with MAPT V337M mutations exhibit impaired control of spontaneous activity.

    “Findings in iPSC-derived neurons with MAPT V337M mutations also exhibit impaired control of spontaneous activity54.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [54] Sohn, P. D. et al. Pathogenic tau impairs axon initial segment plasticity and excitability homeostasis. Neuron 104, 458–470 (2019). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Early dysfunction of glutamatergic neuronal networks is highlighted in previous studies of MAPT V337M HNOs.

    “In addition, early dysfunction of glutamatergic neuronal networks is highlighted in previous studies of MAPT V337M HNOs5.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Bowles, K. R. et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell 184, 4547–4563 (2021). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Our findings coincide with previous literature suggesting tau models can exhibit downregulation of neuronal activity.

    “Our findings coincide with previous literature suggesting tau models can exhibit downregulation of neuronal activity53,54.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [53] Parra Bravo, C. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187, 2446–2464.e22 (2024). source
    • cites [54] Sohn, P. D. et al. Pathogenic tau impairs axon initial segment plasticity and excitability homeostasis. Neuron 104, 458–470 (2019). source

      The Results section on excitability homeostasis reports a significantly lower network burst rate in tauV337M neurons, supporting a decrease in one measure of activity. It does not establish a general downregulation of neuronal activity: firing and single-channel burst rates did not differ significantly, while bursts were longer and more synchronized. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    The HNO model recapitulates some key pathological features of AD and offers greater complexity and translational potential compared to conventional cell and animal models.

    “The HNO model has been shown to recapitulate some of the key pathological features of AD and offers greater complexity and translational potential as compared to conventional cell and animal models92–95.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [92] Seo, J. et al. Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J. Neurosci. 37, 9917–9924 (2017). source
    • cites [93] Gonzalez, C. et al. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol. Psychiatry 23, 2363–2374 (2018). source
    • cites [94] Pavoni, S. et al. Small-molecule induction of Abeta-42 peptide production in human cerebral organoids to model Alzheimer’s disease associated phenotypes. PLoS ONE 13, e0209150 (2018). source
    • cites [95] Gerakis, Y. & Hetz, C. Brain organoids: a next step for humanized Alzheimer’s disease models? Mol. Psychiatry 24, 474–478 (2019). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Modeling 4R tauopathy in human neurons and astrocytes has been implemented, providing a unique platform to investigate the molecular and cellular mechanisms underlying the development and progression of tau pathology with both 3R- and 4R-tau isoforms as seen in FTLD and AD patients.

    “Recently, modeling 4 R tauopathy in human neurons53,83,110,111 and astrocytes110 has been implemented, which provides a unique platform to investigate the molecular and cellular mechanisms underlying the development and progression of tau pathology with both 3R- and 4R-tau isoforms as seen in FTLD and AD patients.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [53] Parra Bravo, C. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187, 2446–2464.e22 (2024). source
    • cites [83] Capano, L. S. et al. Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Cell Stem Cell 29, 918–932 (2022). source

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

      Experimental — accuracy not yet measured
    • cites [110] Bowles, K. R. Development of MAPT S305 mutation human iPSC lines exhibiting elevated 4R tau expression and functional alterations in neurons and astrocytes. Cell Reports 43, 115013 (2024). source
    • cites [111] Manos, J. D. et al. Uncovering specificity of endogenous TAU aggregation in a human iPSC-neuron TAU seeding model. iScience 25, 103658 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Sex-dependent effects of GRAMD1B in FTLD and AD have been shown in animal models and human populations.

    “which has been shown in animal models and human populations113–115.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [113] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source

      The ‘Sex-specific differential response to AD pathology’ section reports sex-dependent transcriptional responses in human AD samples. But the passages do not identify GRAMD1B or report its effects in FTLD or animal models; searches for GRAMD1B and FTLD found no supporting passage. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [114] Fisher, D. W., Bennett, D. A. & Dong, H. Sexual dimorphism in predisposition to Alzheimer’s disease. Neurobiol. Aging 70, 308–324 (2018). source

      The sections on sex–genetics interactions and stress-related signaling in AD describe sex-dependent findings in humans and AD animal models. But the passages do not connect those findings to GRAMD1B or establish them for FTLD; a search for GRAMD1B and FTLD found no such discussion in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [115] Snyder, H. M. et al. Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the Women’s Alzheimer’s Research Initiative. Alzheimers Dement 12, 1186–1196 (2016). source

      The section on sex chromosomes discusses sex-dependent findings in AD mouse models, and the APOE ε4 section discusses findings in humans. Searches for GRAMD1B and FTLD found no passage linking either to the claimed effects in animal models or human populations. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    Human FTLD, AD cases, and PS19 tau mice have increased GRAMD1B expression.

    “Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Mutant HNOs have decreased mean firing rates and number of spikes compared to WT HNOs.

    “We also observe a decrease in mean firing rates and the number of spikes in mutant HNOs compared to WT HNOs (Fig. 3d, e).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Synchronized burst firing activity of mutant HNOs indicated a reduction in spike detection rate (ASDR) and increased interburst intervals compared to WT HNOs.

    “Synchronized burst firing activity of mutant HNOs also indicated a reduction in spike detection rate (ASDR) and increased interburst intervals compared to WT HNOs (Fig. 3g).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    ptau181 was detected in the culture medium of D120 and D60 HNOs.

    “The ptau181 was detected in the medium.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    At D120, IF staining of HNOs revealed a dramatic decrease of cells expressing Ki67, SOX2, or PAX6, and a pronounced increase of cells expressing CTIP2 and SATB2.

    “At D120, IF staining of HNOs revealed a dramatic decrease of cells expressing Ki67, SOX2, or PAX6, and a pronounced increase of cells expressing mature neuronal cell-type and layer architecture markers such as deep-layer neuronal marker (CTIP2) and upper-layer neuronal marker (SATB2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Several DEGs previously associated with lipid metabolism were identified, including MIAT, COMT, NRP1, VEGFB, GRAMD1B, DSEL, and FUT9 associated with glycan structure.

    “We identified several DEGs that have been previously associated with lipid metabolism, including MIAT, COMT, NRP1, VEGFB, GRAMD1B, DSEL56–62, as well as FUT9 associated with glycan structure63,64 (Fig. 4a).”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [56] Mu, F., Wang, Y., Wu, H., You, Q. & Zhang, D. The myocardial infarction-associated transcript 2 inhibits lipid accumulation and promotes cholesterol efflux in oxidized low-density lipoprotein-induced THP-1-derived macrophages via inhibiting mitogen-activated protein kinase signaling and activating the nuclear factor erythroid-related factor 2 signaling pathway. Bioengineered 13, 407–417 (2022). source
    • cites [57] Ye, W. C. et al. Potential therapeutic targeting of lncRNAs in cholesterol homeostasis. Front. Cardiovasc. Med. 8, 688546 (2021). source
    • cites [58] Luo, X. et al. Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1. Mol. Med. Rep. 26, https://doi.org/10.3892/mmr.2022.12801 (2022). source
    • cites [59] Moessinger, C. et al. VEGF-B signaling impairs endothelial glucose transcytosis by decreasing membrane cholesterol content. EMBO Rep. 21, e49343 (2020). source
    • cites [60] Yoshida, T. et al. Association of genetic variants with chronic kidney disease in individuals with different lipid profiles. Int. J. Mol. Med. 24, 233–246 (2009). source
    • cites [61] Salikhova, A. et al. Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways. Circ. Res. 103, e71–e79 (2008). source
    • cites [62] Jiang, Z., Michal, J. J., Wu, X. L., Pan, Z. & MacNeil, M. D. The heparan and heparin metabolism pathway is involved in regulation of fatty acid composition. Int. J. Biol. Sci. 7, 659–663 (2011). source
    • cites [63] Itokazu, Y. & Yu, R. K. Amyloid beta-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and notch signaling. Mol. Neurobiol. 50, 186–196 (2014). source
    • cites [64] Potapenko, I. O. et al. Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression. Mol. Oncol. 4, 98–118 (2010). source

  • It may state two separate claims as one.

    Findingown data

    In N2a cells, GRAMD1B overexpression significantly increases the number of yellow puncta and the number of p62 puncta.

    “GRAMD1B overexpression significantly increased the number of yellow puncta and the number of p62 puncta observed in N2a cells; while reduction of GRAMD1B by shRNA virus reduced both the number of yellow puncta and number of p62 puncta/cell (Supplementary Fig. 8l, m).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In N2a cells, reduction of GRAMD1B by shRNA virus reduces both the number of yellow puncta and number of p62 puncta/cell.

    “GRAMD1B overexpression significantly increased the number of yellow puncta and the number of p62 puncta observed in N2a cells; while reduction of GRAMD1B by shRNA virus reduced both the number of yellow puncta and number of p62 puncta/cell (Supplementary Fig. 8l, m).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Burst activity was altered in mutant organoids compared to isogenic control, with increased interburst intervals and decreased burst firing.

    “Also, burst activity was altered in mutant organoids compared to isogenic control, with increased interburst intervals and decreased burst firing (Fig. 3).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The Aster inhibitor AI-3d can rescue lipid dyshomeostasis, autophagy dysfunction, and tau phosphorylation found in mutant heterozygous HNOs and further decrease levels in control neural organoids without the MAPT mutation.

    “Importantly, we show that the Aster inhibitor, AI-3d can rescue lipid dyshomeostasis, autophagy dysfunction, and tau phosphorylation found in mutant heterozygous HNOs and further decrease levels in control neural organoids without the MAPT mutation (Fig. 8).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    These changes can begin at an early time point, such as Day 60, and be exacerbated by Day 120, evidenced by increased lipid droplets and filipin in mutant heterozygous HNOs compared to controls at Day 120.

    “These changes can begin at an early time point, such as Day 60, and be exacerbated by Day 120, which is evidenced by increased lipid droplets and filipin in mutant heterozygous HNOs compared to controls at Day 120 (Fig. 5j–n).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Alteration of GRAMD1B levels could change the levels of tau phosphorylation, alter autophagy-related proteins PI3K, p-AKT, p62; and alter CDK5R1.

    “We found alteration of GRAMD1B levels could change the levels of tau phosphorylation, alter autophagy-related proteins PI3K, p-AKT, p62; and alter CDK5R1 (Fig. 7 and Supplementary Figs. 8–10).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The MAPT R406W mutation appears to have a profound effect on the cellularity of mutant HNOs, with fewer excitatory neurons and much larger numbers of inhibitory neurons.

    “The MAPT R406W mutation also appears to have a profound effect on the cellularity of mutant HNOs, with fewer excitatory neurons and much larger numbers of inhibitory neurons (Fig. 1e, f)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    For single-cell RNA sequencing analysis, 44,697 single cells were identified encompassing two timepoints and 3 genotypes.

    “For single-cell RNA sequencing analysis, there are 44,697 single cells identified encompassing two timepoints, and 3 genotypes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    MAPT R406W HNOs (HET) exhibit an early disruption of neuroelectrical and network activity, resulting in decreased functional activity compared to WT HNOs.

    “The data suggests that MAPT R406W HNOs (HET) exhibit an early disruption of neuroelectrical and network activity, resulting in a decreased functional activity compared to WT HNOs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    In an AD-mouse model, genetic inhibition of CE by ACAT1 reduces tauopathy.

    “In an AD-mouse model, genetic inhibition of CE by acetyl-CoA acetyltransferase 1 (ACAT1) reduces tauopathy34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Shibuya, Y. et al. Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol. Aging 36, 2248–2259 (2015). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Dyshomeostasis of lipid transport and/or dysfunction of autophagy may play a role in CE dysregulation.

    “Studies suggest the dyshomeostasis of lipid transport35,36 and/or the dysfunction of autophagy may play a role in CE dysregulation37,38.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [35] Yin, F. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. 290, 1420–1453 (2022). source
    • cites [36] Chew, H., Solomon, V. A. & Fonteh, A. N. Involvement of lipids in Alzheimer’s disease pathology and potential therapies. Front. Physiol. 11, 598 (2020). source
    • cites [37] Li, L. et al. Lipids and membrane-associated proteins in autophagy. Protein Cell 12, 520–544 (2021). source
    • cites [38] Dong, H. & Czaja, M. J. Regulation of lipid droplets by autophagy. Trends Endocrinol. Metab. 22, 234–240 (2011). source

  • It may state two separate claims as one.

    Premisecitation

    Increased cholesterol and CE impair autophagic function and tau degradation.

    “Increased cholesterol and CE have been shown to impair autophagic function and tau degradation18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] van der Kant, R. et al. Cholesterol metabolism is a druggable axis that independently regulates tu and amyloid-beta in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 363–375 (2019). source

  • It may state two separate claims as one.

    Premisecitation

    Blocking autophagic flux by Bafilomycin A1 increases tau and lysosomal lipid accumulation.

    “Previous evidence suggests blocking autophagic flux by Bafilomycin A1 increases tau and lysosomal lipid accumulation42–46.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [42] Pollack, S. J. et al. Truncated tau interferes with the autophagy and endolysosomal pathway and results in lipid accumulation. Cell Mol. Life Sci. 81, 304 (2024). source
    • cites [43] Xu, X. et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 18, 816–830 (2013). source
    • cites [44] Tong, B. C. et al. Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies. J. Biomed. Sci. 29, 85 (2022). source
    • cites [45] Vaz-Silva, J. et al. Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction. EMBO J. 37, https://doi.org/10.15252/embj.201899084 (2018). source
    • cites [46] Chen, X. et al. Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy. Mol. Neurodegener. 15, 2 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Many genes with risk alleles for AD involve cholesterol/lipid systems.

    “Genetic studies show that many of the genes which have risk alleles for AD involve cholesterol/lipid systems16,17.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Williams, D. M., Finan, C., Schmidt, A. F., Burgess, S. & Hingorani, A. D. Lipid lowering and Alzheimer disease risk: A mendelian randomization study. Ann. Neurol. 87, 30–39 (2020). source
    • cites [17] Bellenguez, C., Grenier-Boley, B. & Lambert, J. C. Genetics of Alzheimer’s disease: where we are, and where we are going. Curr. Opin. Neurobiol. 61, 40–48 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    MAPT mutations such as MAPT R406W can cause familial FTLD-tau.

    “MAPT mutations such as MAPT R406W can cause familial frontotemporal lobar degeneration with tau (FTLD-tau)1–3.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Mirra, S. S. et al. Tau pathology in a family with dementia and a P301L mutation in tau. J. Neuropathol. Exp. Neurol. 58, 335–345 (1999). source
    • cites [2] Spillantini, M. G., Van Swieten, J. C. & Goedert, M. Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Neurogenetics 2, 193–205 (2000). source
    • cites [3] Karch, C. M. et al. A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies. Stem Cell Rep. 13, 939–955 (2019). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Aster proteins, as well as lipids and lipid droplets, can also be regulated by autophagy.

    “Aster proteins, as well as lipids and lipid droplets, can also be regulated by autophagy37,38.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Li, L. et al. Lipids and membrane-associated proteins in autophagy. Protein Cell 12, 520–544 (2021). source
    • cites [38] Dong, H. & Czaja, M. J. Regulation of lipid droplets by autophagy. Trends Endocrinol. Metab. 22, 234–240 (2011). source

  • Probably not a substantial claim.

    Premisecitation

    Neurons are capable of cholesterol biosynthesis.

    “Nonetheless, neurons are capable of cholesterol biosynthesis30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Suzuki, R. et al. Diabetes and insulin in regulation of brain cholesterol metabolism. Cell Metab. 12, 567–579 (2010). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Previous publications focus on the important role of GRAMD1B in the mouse periphery system such as the adrenal gland and the intestine.

    “Previous publications focus on the important role of GRAMD1B in the mouse periphery system such as the adrenal gland40 and the intestine41.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Sandhu, J. et al. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell 175, 514–529 (2018). source
    • cites [41] Ferrari, A. et al. Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake. Science 382, eadf0966 (2023). source

  • Probably not a substantial claim.

    Premisecitation

    Lipid droplets, primarily composed of neutral lipids such as cholesteryl esters (CE), have been identified at early stages of neurodegenerative diseases.

    “Lipid droplets which are primarily composed of neutral lipid populations such as cholesteryl esters (CE), have been identified at early stages of neurodegenerative diseases10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Farmer, B. C., Walsh, A. E., Kluemper, J. C. & Johnson, L. A. Lipid droplets in neurodegenerative disorders. Front. Neurosci. 14, 742 (2020). source

  • It may state two separate claims as one.

    Premisecitation

    Neurons in tauopathy accumulate lipid droplets and release excess unsaturated lipids, which can be taken up by microglia and result in a pro-inflammatory response and impaired phagocytosis.

    “Interestingly, neurons in tauopathy have been found to accumulate lipid droplets and release excess unsaturated lipids, which can be taken up by microglia and result in a pro-inflammatory response and impaired phagocytosis25.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Li, Y. et al. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK. Cell Metab. 36, 1351–1370 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Statins have been shown to reduce tau pathology in animal models of tauopathy and in CSF from AD patients.

    “In addition, statins, which can lower cholesterol in some reports, has been shown to reduce tau pathology in animal models of tauopathy19 and in cerebrospinal fluid (CSF) from AD patients20.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Boimel, M. et al. Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy. J. Neuropathol. Exp. Neurol. 68, 314–325 (2009). source
    • cites [20] Riekse, R. G. et al. Effect of statins on Alzheimer’s disease biomarkers in cerebrospinal fluid. J. Alzheimers Dis. 10, 399–406 (2006). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Neurons are preferentially vulnerable to tau pathology in tauopathies, including FTLD and AD.

    “Neurons are preferentially vulnerable to tau pathology in a group of diseases known as tauopathies, including FTLD and AD, a secondary tauopathy31,55.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019). source
    • cites [55] Chen, S. et al. Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease. Acta Neuropathol. Commun. 10, https://doi.org/10.1186/s40478-022-01494-6 (2022). source

  • It may state two separate claims as one.

    Interpretationcitation

    CE dysregulation could be an upstream driver of tau pathology and processes mediating neuronal CE levels may be a therapeutic target to prevent aberrant ptau accumulation in AD and potentially other tauopathies.

    “These data suggest that CE dysregulation could be an upstream driver of tau pathology and that processes which mediate neuronal CE levels may be a therapeutic target to prevent aberrant ptau accumulation in AD and potentially other tauopathies.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    GRAMD1B may play a relevant role in neurodegeneration by increasing tau phosphorylation via disrupting lipid homeostasis and autophagy and increasing CDK5R1.

    “We found GRAMD1B may play a relevant role in neurodegeneration by increasing tau phosphorylation via disrupting lipid homeostasis and autophagy and increasing CDK5R1.”
    • Also stated in: § Discussion · hedged
      “In this paper, we demonstrate that GRAMD1B may play a relevant role in neurodegeneration by increasing tau phosphorylation via disrupting lipid homeostasis and autophagy and increasing CDK5R1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Cholesterol dysregulation and lipid dyshomeostasis have been identified in several neurodegenerative diseases.

    “Importantly, cholesterol dysregulation6–9 and lipid dyshomeostasis8,10–15 have been identified in several neurodegenerative diseases.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [6] Mori, T. et al. Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J. Neuropathol. Exp. Neurol. 60, 778–785 (2001). source
    • cites [7] Wolozin, B. Cholesterol and Alzheimer’s disease. Biochem. Soc. Trans. 30, 525–529 (2002). source
    • cites [8] Di Paolo, G. & Kim, T. W. Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat. Rev. Neurosci. 12, 284–296 (2011). source
    • cites [9] Abisambra, J. F. et al. LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer’s disease. PLoS ONE 5, e8556 (2010). source
    • cites [10] Farmer, B. C., Walsh, A. E., Kluemper, J. C. & Johnson, L. A. Lipid droplets in neurodegenerative disorders. Front. Neurosci. 14, 742 (2020). source
    • cites [11] Yang, D. et al. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci. 12, 106 (2022). source
    • cites [12] Kim, W. S. et al. Lipidomics analysis of behavioral variant frontotemporal dementia: A scope for biomarker development. Front Neurol. 9, 104 (2018). source
    • cites [13] Phan, K. et al. Uncovering pathophysiological changes in frontotemporal dementia using serum lipids. Sci. Rep. 10, 3640 (2020). source
    • cites [14] Ahmed, R. M. et al. Systemic metabolism in frontotemporal dementia. Neurology 83, 1812–1818 (2014). source
    • cites [15] Godoy-Corchuelo, J. M. et al. Lipid metabolic alterations in the ALS-FTD spectrum of disorders. Biomedicines 10, https://doi.org/10.3390/biomedicines10051105 (2022). source

  • It may state two separate claims as one.

    Interpretationcitation

    Increased total tau at D120 indicates maturation of HNOs since increased neuronal growth occurs in parallel with increased total tau expression.

    “Increased total tau at D120 also indicates the maturation of HNOs since the increased neuronal growth will occur in parallel with increased total tau expression51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Iovino, M. et al. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain 138, 3345–3359 (2015). source

  • It may state two separate claims as one.

    Interpretationown data

    The findings elucidate the role of GRAMD1B in the nervous system and highlight its relevance to FTLD and AD.

    “Our findings elucidate the role of GRAMD1B in the nervous system and highlight its relevance to FTLD and AD.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    GRAMD1B is capable of modulating tau phosphorylation levels and autophagy-related protein p62 in vitro.

    “suggesting GRAMD1B is capable of modulating tau phosphorylation levels and autophagy-related protein, p62, in vitro.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Both pieces of data are in line with scRNA-seq results, which shows HMGCS1 decreases in mutant heterozygous HNOs within the Deep Layer Excitatory Neuronal subcluster, while SREBP2 is not a DEG and is not changed.

    “Both pieces of data are in line with our scRNA-seq results, which shows HMGCS1 decreases in our mutant heterozygous HNOs within the Deep Layer Excitatory Neuronal subcluster (Supplementary Fig. 2c), while SREBP2 is not a DEG and is not changed.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The data suggests that increased GRAMD1B expression can alter lipid homeostasis by increasing free cholesterol lipid droplets and altering cholesterol biosynthesis-related proteins.

    “The data suggests that increased GRAMD1B expression can alter lipid homeostasis by increasing free cholesterol lipid droplets and altering cholesterol biosynthesis-related proteins.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Transcriptomic level changes of GRAMD1B can be observed on the protein level of GRAMD1B expression and is present in tandem with increased free cholesterol and lipid droplet formation in mutant heterozygous HNOs.

    “Therefore, transcriptomic level changes of GRAMD1B can be observed on the protein level of GRAMD1B expression and is present in tandem with increased free cholesterol and lipid droplet formation in mutant heterozygous HNOs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Previous studies have associated alterations of cholesterol and lipid metabolism in FTLD brain tissue and serum/plasma samples.

    “Previous studies have associated alterations of cholesterol and lipid metabolism in FTLD brain tissue72 and serum/plasma samples12,13.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [72] Marian, O. C. et al. Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta Neuropathol. Commun. 11, 52 (2023). source
    • cites [12] Kim, W. S. et al. Lipidomics analysis of behavioral variant frontotemporal dementia: A scope for biomarker development. Front Neurol. 9, 104 (2018). source
    • cites [13] Phan, K. et al. Uncovering pathophysiological changes in frontotemporal dementia using serum lipids. Sci. Rep. 10, 3640 (2020). source

  • It may state two separate claims as one.

    Interpretationown data

    The data mirrors observations in mutant heterozygous HNOs, which also exhibit increased GRAMD1B gene expression and protein expression in tandem with increased filipin, increased lipid droplets, decreased HMGCS1, and no change in SREBP2.

    “Importantly, the data mirrors our observations in mutant heterozygous HNOs, which also exhibit increased GRAMD1B gene expression and protein expression in tandem with increased filipin, increased lipid droplets, decreased HMGCS1, and no change in SREBP2 (Fig. 5j–n).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The presence of yellow puncta suggests autophagic flux is being blocked by inhibition of lysosome fusion with the autophagosome, and can be induced by Bafilomycin A1.

    “The presence of yellow puncta suggests autophagic flux is being blocked by inhibition of lysosome fusion with the autophagosome74–77, and can be induced by the addition of autophagy blocker, Bafilomycin A1 (BAFA1) (Supplementary Fig. 8k).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [74] Zhang, H., Knight, C., Chen, S. R. W. & Bezprozvanny, I. A gating mutation in ryanodine receptor type 2 rescues phenotypes of Alzheimer’s disease mouse models by upregulating neuronal autophagy. J. Neurosci. 43, 1441–1454 (2023). source
    • cites [75] Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)(1). Autophagy 17, 1–382 (2021). source
    • cites [76] Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359, 1277–1283 (2018). source
    • cites [77] Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004). source

  • It may state two separate claims as one.

    Study design and conductown data

    The FUW-mCherry-GFP-LC3 system was validated in mouse neuroblastoma N2a cells in the presence of BAFA1 and co-stained with p62.

    “The FUW-mCherry-GFP-LC3 system was validated in mouse neuroblastoma, N2a cells, in the presence of BAFA1and were co-stained with p62 (Supplementary Fig. 8l, m).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Degradation of both lipids and tau protein is regulated by autophagy.

    “Given the degradation of both lipids and tau protein is regulated by autophagy37,38”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Li, L. et al. Lipids and membrane-associated proteins in autophagy. Protein Cell 12, 520–544 (2021). source
    • cites [38] Dong, H. & Czaja, M. J. Regulation of lipid droplets by autophagy. Trends Endocrinol. Metab. 22, 234–240 (2011). source

  • It may state two separate claims as one.

    Interpretationcitation

    Observed changes in cholesterol, CE, and lipid metabolism support previous observations of altered lipid metabolism in FTLD patient tissue samples, which may contribute to development of tau pathology at early stages.

    “The observed changes in cholesterol, CE, and lipid metabolism in this study support previous observations of altered lipid metabolism in FTLD patient tissue samples12,13,72, which may contribute to the development of tau pathology at the early stages of the disease.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Kim, W. S. et al. Lipidomics analysis of behavioral variant frontotemporal dementia: A scope for biomarker development. Front Neurol. 9, 104 (2018). source
    • cites [13] Phan, K. et al. Uncovering pathophysiological changes in frontotemporal dementia using serum lipids. Sci. Rep. 10, 3640 (2020). source
    • cites [72] Marian, O. C. et al. Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta Neuropathol. Commun. 11, 52 (2023). source

  • It may state two separate claims as one.

    Interpretationown data

    Both increased cholesterol and increased GRAMD1B alter autophagic flux.

    “The data, together with a significant increase of p62 by GRAMD1B alone, indicates both increased cholesterol and increased GRAMD1B alter autophagic flux.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    GRAMD1B is a member of the Aster family and a known cholesterol transporter.

    “GRAMD1B is a member of the Aster family and a known cholesterol transporter40,66.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Sandhu, J. et al. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell 175, 514–529 (2018). source
    • cites [66] Ferrari, A. et al. Aster proteins regulate the accessible cholesterol pool in the plasma membrane. Mol. Cell. Biol. 40, https://doi.org/10.1128/MCB.00255-20 (2020). source

  • It may state two separate claims as one.

    Premisecitation

    GRAMD1B has been shown to alter the PI3K-pAKT pathway, which, if activated, can block autophagy.

    “Importantly, GRAMD1B has been shown to alter the PI3K-pAKT pathway, which, if activated, can block autophagy78,79.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Khanna, P., Lee, J. S., Sereemaspun, A., Lee, H. & Baeg, G. H. GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling. Sci. Rep. 8, 9511 (2018). source
    • cites [79] Ng, M. Y. W. et al. The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics. Nat. Commun. 13, 6283 (2022). source

  • It may state two separate claims as one.

    Interpretationown data

    The MAPT R406W mutation may inhibit neuronal activity and disrupt the neuronal network.

    “Our results suggest the MAPT R406W mutation may inhibit neuronal activity and disrupt the neuronal network.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Blocking autophagic flux by Bafilomycin A1 increases tau and lysosomal lipid accumulation, while increased cholesterol and CE impairs autophagy function and tau degradation.

    “Blocking autophagic flux by Bafilomycin A1 increases tau and lysosomal lipid accumulation84, while increased cholesterol and CE impairs autophagy function and tau degradation18,27.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Mauvezin, C. & Neufeld, T. P. Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy 11, 1437–1438 (2015). source
    • cites [18] van der Kant, R. et al. Cholesterol metabolism is a druggable axis that independently regulates tu and amyloid-beta in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 363–375 (2019). source
    • cites [27] Wang, T. et al. High cholesterol and 27-hydroxycholesterol contribute to phosphorylation of tau protein by impairing autophagy causing learning and memory impairment in C57BL/6J mice. J. Nutr. Biochem. 106, 109016 (2022). source

  • It may state two separate claims as one.

    Interpretationreasoning

    GRAMD1B plays a role in disease-associated mechanisms, such as lipid dyshomeostasis, autophagy dysfunction, and tau phosphorylation; and may be a player in neurodegenerative diseases such as FTLD and AD.

    “In this way, GRAMD1B plays a role in disease-associated mechanisms, such as lipid dyshomeostasis, autophagy dysfunction, and tau phosphorylation; and may be a player in neurodegenerative diseases such as FTLD and AD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Lipid dyshomeostasis has been found in MAPT R406W mutant HNOs and FTLD as well as AD and related dementias, including dysregulation of cholesterol biosynthesis, uptake, storage, and transport.

    “Lipid dyshomeostasis has been found in MAPT R406W mutant HNOs and FTLD as well as AD and related dementias4,10, including the dysregulation of cholesterol biosynthesis, uptake, storage, and transport.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Glasauer, S. M. K. et al. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Rep. 17, 2127–2140 (2022). source
    • cites [10] Farmer, B. C., Walsh, A. E., Kluemper, J. C. & Johnson, L. A. Lipid droplets in neurodegenerative disorders. Front. Neurosci. 14, 742 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    The changes in our observations compared to previously reported DEGs may be due to differences in culture methods and time points at which HNOs were studied, which may yield different cell type populations and a different number of astrocytes.

    “The changes in our observations compared to the previously reported DEG’s may be due to differences in culture methods and time points at which HNOs were studied, which may yield different cell type populations and a different number of astrocytes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Premisecitation

    This explanation is consistent with previous publications.

    “This explanation is consistent with previous publications81,82.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Spires-Jones, T. L., Kopeikina, K. J., Koffie, R. M., de Calignon, A. & Hyman, B. T. Are tangles as toxic as they look? J. Mol. Neurosci. 45, 438–444 (2011). source
    • cites [82] Zwang, T. J. et al. Neurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer’s pathology. Cell Rep. 43, 114574 (2024). source

  • Probably not a substantial claim.

    Premisecitation

    Excitatory neuronal populations are a vulnerable cell type in human FTLD and AD cases.

    “Excitatory neuronal populations are a vulnerable cell type in human FTLD and AD cases31,55.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019). source
    • cites [55] Chen, S. et al. Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease. Acta Neuropathol. Commun. 10, https://doi.org/10.1186/s40478-022-01494-6 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Increased phosphorylation of tau has been observed in HNOs and iPSC-derived neurons with MAPT mutations.

    “Increased phosphorylation of tau has been observed in HNOs and iPSC-derived neurons with the MAPT mutations5,86.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Bowles, K. R. et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell 184, 4547–4563 (2021). source
    • cites [86] Mahali, S. et al. Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration. Transl. Psychiatry 12, 508 (2022). source

  • It may state two separate claims as one.

    Interpretationown data

    Both the PI3K-pAKT pathway is activated and autophagy is being blocked in mutant HNOs.

    “suggesting both the PI3K-pAKT pathway is activated and autophagy is being blocked.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    AI-3d has been found to inhibit cholesterol uptake and maintain lipid homeostasis.

    “AI-3d has been found to inhibit cholesterol uptake and maintain lipid homeostasis40,66.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Sandhu, J. et al. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell 175, 514–529 (2018). source
    • cites [66] Ferrari, A. et al. Aster proteins regulate the accessible cholesterol pool in the plasma membrane. Mol. Cell. Biol. 40, https://doi.org/10.1128/MCB.00255-20 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    No further investigation into the functional activity of HNOs, autophagy function, lipid droplet accumulation, or mechanism of tau phosphorylation was performed in that study.

    “However, no further investigation into the functional activity of HNOs, autophagy function, lipid droplet accumulation, or mechanism of tau phosphorylation was performed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Glasauer, S. M. K. et al. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Rep. 17, 2127–2140 (2022). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Increases in neuronal CE drive ptau accumulation in hiPSCs-derived AD neurons; statins reduce tau pathology in animal models of tauopathy and in CSF from AD patients; and genetic inhibition of CE by ACAT1 reduces tauopathy in an AD-mouse model.

    “Increases in neuronal CE drive ptau accumulation in hiPSCs-derived AD neurons18–21; while statins, a class of lipid-lowering medications, reduce tau pathology in animal models of tauopathy19 and in cerebrospinal fluid (CSF) from AD patients20, and genetic inhibition of CE by acetyl-CoA acetyltransferase 1 (ACAT1) reduces tauopathy in an AD-mouse model21.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [18] van der Kant, R. et al. Cholesterol metabolism is a druggable axis that independently regulates tu and amyloid-beta in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 363–375 (2019). source
    • cites [19] Boimel, M. et al. Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy. J. Neuropathol. Exp. Neurol. 68, 314–325 (2009). source
    • cites [20] Riekse, R. G. et al. Effect of statins on Alzheimer’s disease biomarkers in cerebrospinal fluid. J. Alzheimers Dis. 10, 399–406 (2006). source
    • cites [21] Shibuya, Y., Chang, C. C. & Chang, T. Y. ACAT1/SOAT1 as a therapeutic target for Alzheimer’s disease. Future Med. Chem. 7, 2451–2467 (2015). source

  • It may state two separate claims as one.

    Interpretationown data

    Increased GRAMD1B expression may alter cholesterol transport, increase both free cholesterol and CE, activate the PI3K-pAKT pathway to block autophagy, and increase CDK5R1 expression; all of which may contribute to increased tau phosphorylation and accumulation.

    “Increased GRAMD1B expression may alter cholesterol transport, increase both free cholesterol and CE, activate the PI3K-pAKT pathway to block autophagy, and increase CDK5R1 expression; all of which may contribute to increased tau phosphorylation and accumulation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The MAPT R406W mutation may induce lipid dyshomeostasis, which may trigger an increase in GRAMD1B expression.

    “Together our data suggests that the MAPT R406W mutation may induce lipid dysomeostasis, which may trigger an increase in GRAMD1B expression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    A potential reason for decreased free cholesterol in culture media of mutant heterozygous HNOs is that they exhibit a reduction in cholesterol efflux.

    “A potential reason for decreased free cholesterol in the culture media of mutant heterozygous HNOs is that they exhibit a reduction in cholesterol efflux.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Lipid dyshomeostasis correlates with tau pathology and cognitive deficits in these diseases.

    “Importantly, lipid dyshomeostasis correlates with tau pathology and cognitive deficits in these diseases6,8,29.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Mori, T. et al. Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J. Neuropathol. Exp. Neurol. 60, 778–785 (2001). source
    • cites [8] Di Paolo, G. & Kim, T. W. Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat. Rev. Neurosci. 12, 284–296 (2011). source
    • cites [29] Nanjundaiah, S., Chidambaram, H., Chandrashekar, M. & Chinnathambi, S. Role of microglia in regulating cholesterol and tau pathology in Alzheimer’s disease. Cell Mol. Neurobiol. 41, 651–668 (2021). source

  • It may state two separate claims as one.

    Interpretationreasoning

    The decreased GRAMD1B, filipin, and lipid droplets in PHF1+ cells suggest that tangle-like tau pathology may induce a compensatory response by reducing the burden of GRAMD1B, filipin, and lipid droplets in those neurons, which may make them less vulnerable to pathological tau toxicity.

    “The decreased GRAMD1B, filipin, and lipid droplets in PHF1 + cells suggest that tangle-like tau pathology may induce a compensatory response by reducing the burden of GRAMD1B, filipin, and lipid droplets in those neurons, which may make them less vulnerable to pathological tau toxicity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The scRNA-seq data within their study highlighted cholesterol-related changes in astrocytes, while glycolytic changes were highlighted in neuronal populations.

    “The scRNA-seq data within their study highlighted cholesterol-related changes in astrocytes, while glycolytic changes were highlighted in neuronal populations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Glasauer, S. M. K. et al. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Rep. 17, 2127–2140 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationreasoning

    The reduction in cholesterol efflux may be a result of cholesterol being transported from the plasma membrane to the endoplasmic reticulum by proteins such as GRAMD1B and therein converted to CE.

    “The reduction in cholesterol efflux may be a result of cholesterol being transported from the plasma membrane to the endoplasmic reticulum by proteins such as GRAMD1B and therein converted to CE.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Reduction or inhibition of GRAMD1B may reverse the lipid dysregulation, altered autophagy, and increased tau phosphorylation observed in mutant heterozygous HNOs.

    “Together, our observations suggest reduction or inhibition of GRAMD1B may reverse the lipid dysregulation, altered autophagy, and increased tau phosphorylation observed in mutant heterozygous HNOs.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    CE could be an upstream driver of tau pathology and neuronal CE may be a therapeutic target to prevent aberrant ptau accumulation in AD and potentially other tauopathies.

    “These data suggest that CE could be an upstream driver of tau pathology and that neuronal CE may be a therapeutic target to prevent aberrant ptau accumulation in AD and potentially other tauopathies.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    GRAMD1B may regulate the PI3K/p-AKT pathway and autophagic flux, contributing to the accumulation of CE and pathological tau species in neurons.

    “Our results suggest that GRAMD1B may regulate the PI3K/p-AKT pathway and autophagic flux, contributing to the accumulation of CE and pathological tau species in neurons.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    GRAMD1B modulation can alter key players in blocking autophagy, including PI3K phospho-AKT, as well as alter autophagy flux and p62.

    “Overall, these data suggest GRAMD1B modulation can alter key players in blocking autophagy, including PI3K phospho-AKT, as well as alter autophagy flux and p62.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All experiments consisted of an appropriate number of sections, organoids, neurons, and animals, as listed in the figure legends.

    “All experiments consisted of an appropriate number of sections, organoids, neurons, and animals, as listed in the figure legends.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Quality check of dilated ROIs and dots being counted was performed for each round.

    “Quality check of dilated ROI’s and dots being counted was performed for each round.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    The sample size for quantifying organoids, neurons, and single-mRNA molecules was based on previous publications.

    “The sample size for quantifying organoids, neurons, and single-mRNA molecules was based on previous publications.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    For every experiment, sections, coverslips, and individual cells within each group were selected at random for analysis.

    “For every experiment, sections, coverslips, and individual cells within each group were selected at random for analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductreasoning

    smFISH analysis was performed via a custom script for the cortical layer of the organoid, and counting was done without human interference.

    “smFISH analysis was performed via a custom script for the cortical layer of the organoid and so counting was done without human interference.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The study was approved by the Washington University School of Medicine and the University of California San Francisco IRB and Ethics Committee.

    “was approved by the Washington University School of Medicine and the University of California San Francisco IRB and Ethics Committee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Due to a lower number of cells with lipid droplet staining in the control organoids, 10 cells were selected for each organoid section to match the number of cells that were able to be visualized with clear lipid droplet staining.

    “Due to a lower number of cells with lipid droplet staining in the control organoids, 10 cells were selected for each organoid section to match the number of cells that were able to be visualized with clear lipid droplet staining.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The lack of 4R-tau in our HNO culture may be due to the nature of developmental organoid culture lacking the aging phenotype.

    “The lack of 4R-tau may be also due to the nature of developmental organoid culture lacking the aging phenotype.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Staining was performed by at least three individuals.

    “Staining was performed by at least three individuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisereasoning

    The human iPSCs used in the study were generated from skin biopsies donated by patients with the MAPT R406W mutation.

    “Human induced pluripotent stem cells were attained from The Tau Consortium, which provides induced pluripotent stem cells (iPSCs) generated from skin biopsies donated by patients with the MAPT R406W mutation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Skin biopsies were collected with written informed consent.

    “Skin biopsies were collected with written informed consent”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    We have applied the AggreWellTM800 culture method and can reproduce several of our initial findings using IF with two different culture methods.

    “Importantly, we have applied this culture method and can reproduce several of our initial findings using IF with two different culture methods.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All experiments follow approved animal protocols by the national guidelines provided by the NIH and by the IACUC of the Ohio State University.

    “All experiments follow approved animal protocols by the national guidelines provided by the National Institutes of Health (NIH) and by the Institutional Animal Care and Use Committee (IACUC) of the Ohio State University.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Time points for scRNA-seq were selected based on previous literature suggesting these are time points at which changes in organoid maturation can be observed.

    “Time points were selected based on previous literature that utilizes neural organoids for immunostaining and transcriptomic analysis4,5,47, suggesting these are time points at which changes in organoid maturation can be observed.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Glasauer, S. M. K. et al. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Rep. 17, 2127–2140 (2022). source
    • cites [5] Bowles, K. R. et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell 184, 4547–4563 (2021). source
    • cites [47] Bhaduri, A. et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature 578, 142–148 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Our current protocol of HNO culture does not incorporate a vascular system or mature oligodendrocytes.

    “In addition, our current protocol of HNO culture does not incorporate a vascular system or mature oligodendrocytes”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    Due to the use of MEA, our analysis is performed based on channel activity and is more appropriate for understanding local field potential (LFP) changes than single unit functional activity.

    “Lastly, due to the use of MEA, our analysis is performed based on channel activity and is more appropriate for understanding local field potential (LFP) changes than single unit (aka single cell) functional activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    Validation of GRAMD1B antibody for immunostaining was performed using GRAMD1B KO intestinal scrapings from mouse who have been gene-edited to knockout GRAMD1B.

    “Validation of GRAMD1B antibody for immunostaining was performed using GRAMD1B KO intestinal scrapings from mouse who have been gene-edited to knockout GRAMD1B and were kindly shared by Dr. Peter Tontonotz.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    The PHF1 antibody has been extensively validated by previous publications.

    “The PHF1 antibody was kindly provided by Dr. Peter Davies and has been extensively validated by previous publications as described in the link: https://www.alzforum.org/antibodies/tau-phos-ser396ser404-phf-1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No data were excluded from the analyses.

    “No data were excluded from the analyses;”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The analysis is blinded if not automated with the appropriate software.

    “The analysis is blinded if not automated with the appropriate software.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Progerin has been previously demonstrated to induce late-onset age-related disease features in human iPSC-based disease models.

    “Progerin has been previously demonstrated to induce late-onset age-related disease features in human iPSC-based disease models112.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Miller, J. D. et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13, 691–705 (2013). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Each experiment was repeated independently at least three times, with similar results.

    “Each experiment was repeated independently at least three times.”
    • Also stated in: § Statistical analysis and reproducibility · plain
      “A minimum of three independent experiments were repeated with similar results.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Our findings are consistent with reduced neuronal activity in tau transgenic mice and the negative correlation of tauopathy measured by PET tau tracer with neuronal activity measured with FDG PET.

    “Our findings are also consistent with reduced neuronal activity in tau transgenic mice53 and the negative correlation of tauopathy measured by PET tau tracer with neuronal activity measured with FDG PET87.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Parra Bravo, C. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187, 2446–2464.e22 (2024). source
    • cites [87] Zhang, K. et al. PET imaging of neural activity, beta-amyloid, and tau in normal brain aging. Eur. J. Nucl. Med. Mol. Imaging 48, 3859–3871 (2021). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductreasoning

    Human postmortem brain specimens were obtained by consent at autopsy, de-identified, and IRB-exempt.

    “These specimens were obtained by consent at autopsy and have been de-identified and are IRB-exempt to protect the identity of each patient.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The potential reason of reduced neuronal activity in neurons accumulated with pathological tau is the repression of translation by abnormal tau accumulation.

    “The potential reason of reduced neuronal activity in neurons accumulated with pathological tau is the repression of translation91 by abnormal tau accumulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Koren, S. A., Galvis-Escobar, S. & Abisambra, J. F. Tau-mediated dysregulation of RNA: Evidence for a common molecular mechanism of toxicity in frontotemporal dementia and other tauopathies. Neurobiol. Dis. 141, 104939 (2020). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Antibodies used were validated by the company whose information is provided in the methods.

    “Antibodies were validated by the company whose information is provided in the methods.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    HNOs that incorporate microglia promote maturation and provide unique advantages as in vitro neuroimmune models.

    “Despite the limitations of organoid-based models, HNOs that incorporate microglia promote maturation97 and provide unique advantages as in vitro neuroimmune models98–103, which are increasingly becoming utilized.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [97] Park, D. S. et al. iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer. Nature 623, 397–405 (2023). source
    • cites [98] Abud, E. M. et al. iPSC-Derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293 (2017). source
    • cites [99] Han, C. Z. et al. Human microglia maturation is underpinned by specific gene regulatory networks. Immunity 56, 2152–2171 (2023). source
    • cites [100] Chichagova, V. et al. Incorporating microglia-like cells in human induced pluripotent stem cell-derived retinal organoids. J. Cell. Mol. Med. 27, 435–445 (2023). source
    • cites [101] Victor, M. B. et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell 29, 1197 (2022). source
    • cites [102] Cakir, B. et al. Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids. Nat. Commun. 13, 430 (2022). source
    • cites [103] Cakir, B., Kiral, F. R. & Park, I. H. Advanced in vitro models: Microglia in action. Neuron 110, 3444–3457 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    HNOs may be used as a complementary model for animal models.

    “Thus, it may be used as a complementary model for animal models.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Study design and conductreasoning

    Blinding is not relevant to staining experiments as samples are all processed together and under the same conditions.

    “Blinding is not relevant to staining experiments as samples are all processed together and under the same conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The investigators were not blinded to allocation during experiments but were blinded to outcome assessment.

    “The Investigators were not blinded to allocation during experiments but were blinded to outcome assessment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The sample size is reported in each figure legend.

    “The sample size is reported in each figure legend.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductreasoning

    We minimize variability by choosing similar sizes of healthy embryoid bodies during the encapsulation stage and for experiments, and HNOs of similar size and shape were selected for each experiment.

    “We minimize variability by choosing similar sizes of healthy embryoid bodies during the encapsulation stage and for experiments.”
    • Also stated in: § Human neural organoid (HNO) culture · plain
      “HNOs of similar size and shape were selected for each experiment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Recording of Microelectrode Arrays was performed blindly.

    “Recording of Microelectrode Arrays was performed blindly.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    For single-cell RNA sequencing on human neural organoids, each independent experiment consisted of two individual replicates per genotype for a total of six samples per independent experiment (12 samples for both independent experiments).

    “For single-cell RNA sequencing on human neural organoids, each independent experiment consisted of two individual replicates per genotype for a total of six samples per independent experiment (12 samples for both independent experiments).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Due to limitation in the availability of hiPSCs with the MAPT R406W mutation, we used the same gender of hiPSCs to generate HNOs and a different patient line for the MAPT R406W homozygous iPSC line.

    “In addition, due to the limitation in the availability of hiPSCs with the MAPT R406W mutation, we used the same gender of hiPSCs to generate HNOs and a different patient line for the MAPT R406W homozygous iPSC line”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    GRAMD1B could be another potential therapeutic target against FTLD and AD.

    “Our results suggest that GRAMD1B could be another potential therapeutic target against FTLD and AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Study design and conductnone given

    Careful consideration and planning were done regarding the use of different animal species and concentrations for primary antibodies that would be used for Multiplexed IF.

    “Careful consideration and planning were done regarding the use of different animal species and concentrations for primary antibodies that would be used for Multiplexed IF.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Some limitations in our functional studies include a lack of spatial resolution of our recordings as well as limited time course recordings.

    “Some limitations in our functional studies include a lack of spatial resolution of our recordings as well as limited time course recordings, which may aid our understanding of functional activity changes over time in our HNO models.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Changes in GRAMD1B expression were validated by IF staining.

    “Changes in GRAMD1B expression were validated by IF staining.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The experiments were randomized.

    “The experiments were randomized;”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Established unguided methods of spontaneous HNO culture, including the one used in this study, may introduce variability, stress, and cell death.

    “However, established unguided methods of spontaneous HNO culture, including the one used in this study48, may introduce variability, stress, and cell death96.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Lancaster, M. A. & Knoblich, J. A. Generation of cerebral organoids from human pluripotent stem cells. Nat. Protoc. 9, 2329–2340 (2014). source
    • cites [96] Bertucci, T. et al. Improved protocol for reproducible human cortical organoids reveals early alterations in metabolism with MAPT mutations. Preprint at https://doi.org/10.1101/2023.07.11.548571 (2023). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The hypoexcitability induced by tau pathology is different from the hyperactivity induced by APP or PSEN mutations, which increases Aβ pathology in AD.

    “The hypoexcitability induced by tau pathology is different from the hyperactivity induced by APP or PSEN mutations88–90, which increases Aβ pathology in AD.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [88] Palop, J. J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711 (2007). source
    • cites [89] Busche, M. A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321, 1686–1689 (2008). source
    • cites [90] Tu, H. et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126, 981–993 (2006). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Vascular system and mature oligodendrocytes play an important role in neurodevelopment and neurodegenerative diseases like AD.

    “which have been demonstrated to play an important role in neurodevelopment and neurodegenerative diseases like AD108.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Canepa, E. & Fossati, S. Impact of tau on neurovascular pathology in Alzheimer’s disease. Front. Neurol. 11, 573324 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The generation of cDNA libraries for single-cell RNA sequencing and analysis was performed blindly using coded samples.

    “The generation of cDNA libraries for single-cell RNA sequencing and analysis was performed blindly using coded samples.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Microelectrode array recording analysis was performed on active channels (greater than 5 identified spikes) or otherwise discarded.

    “Microelectrode array recording analysis was performed on active channels (greater than 5 identified pikes) or otherwise discarded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductcitation

    smFISH experimental analysis was performed by a custom script, and cells containing less than 5 single-mRNA molecules (dots) were removed from analysis following previous publication guidelines.

    “smFISH experimental analysis was performed by a custom script, cells which contained less than 5 single-mRNA molecules (dots) were removed from analysis following previous publication guidelines.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Sample sizes were based on preliminary data, previous successful experiments routinely performed in the lab, and previous publications utilizing human neural organoids.

    “Sample sizes were based on preliminary data, previous successful experiments routinely performed in the lab, and previous publications utilizing human neural organoids.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Recent advances using the AggreWellTM800 Microwell or similar culture plates have provided easy and reproducible production of HNOs.

    “Recent advances using the AggreWell™800 Microwell or similar culture plates have provided easy and reproducible production of HNOs96.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Bertucci, T. et al. Improved protocol for reproducible human cortical organoids reveals early alterations in metabolism with MAPT mutations. Preprint at https://doi.org/10.1101/2023.07.11.548571 (2023). source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Study design and conductnone given

    The size of organoids, culture days, age, and conditions were controlled for between experimental groups.

    “The size of organoids, culture days, age, and conditions were controlled for between experimental groups.”
    Quote in the paperNot a substantial claim
132 of 132

  • The paper relies on this without support.

    The relationship between lipid dyshomeostasis and tau pathology remains unclear.

    “However, the relationship between lipid dyshomeostasis and tau pathology remains unclear.”

  • The paper relies on this without support.

    It is not fully understood how cholesterol changes may mediate tau pathology.

    “However, it is not fully understood how cholesterol changes may mediate tau pathology.”

  • The paper relies on this without support.

    Most studies on cholesterol and tau focus on astrocyte and microglia populations.

    “Although several studies suggest a relationship between tau, post-translational modifications, and changes in cholesterol4,18,26–29, most studies focus on astrocyte and microglia populations, given their primary role in cholesterol biosynthesis.”

  • The paper relies on this without support.

    Cholesterol transport in neurons is largely unexplored.

    “Nonetheless, neurons are capable of cholesterol biosynthesis30, and cholesterol transport in neurons is largely unexplored.”

  • The paper relies on this without support.

    The mechanism in which CE dysregulation occurs in diseases such as FTLD and AD is still under investigation.

    “However, the mechanism in which CE dysregulation occurs in diseases such as FTLD and AD, is still under investigation.”

  • The paper relies on this without support.

    The role of nonvesicular lipid transport, particularly Aster proteins, in FTLD and AD and their relationships with autophagy, lipid homeostasis, and tau accumulation, remain unknown.

    “The role of nonvesicular lipid transport, particularly Aster proteins, in FTLD and AD and their relationships with autophagy, lipid homeostasis, and tau accumulation, remain unknown.”

  • The paper relies on this without support.

    The functional role of GRAMD1B in excitatory neurons is largely unknown.

    “However, the functional role of GRAMD1B in excitatory neurons is largely unknown.”

  • The paper relies on this without support.

    GRAMD1B has not been shown in association with any tau models or human patient cases with FTLD and AD until now.

    “Importantly, GRAMD1B has not been shown in association with any tau models or human patient cases with FTLD and AD until now.”

  • The paper relies on this without support.

    Such a role for GRAMD1B has not yet been published and has not been described in any disease model.

    “This represents a significant finding since such a role for GRAMD1B has not yet been published and has not been described in any disease model.”

  • The paper relies on this without support.

    The molecular mechanisms underlying the correlation between lipid dyshomeostasis and tau pathology remain unknown.

    “However, the molecular mechanisms underlying this correlation remain unknown.”

  • The paper relies on this without support.

    No further investigation into the functional activity of HNOs, autophagy function, lipid droplet accumulation, or mechanism of tau phosphorylation was performed in the prior study.

    “However, no further investigation into the functional activity of HNOs, autophagy function, lipid droplet accumulation, or mechanism of tau phosphorylation was performed.”
11 of 11

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.

  • AI-3d treatment concentration differs by 1,000-fold

    Major

    The Fig. 8 legend says the organoids received 3 mM AI-3d, whereas the Methods specify 3 μM for the same one-week treatment.

  • MEA organoid counts disagree

    Major

    The Fig. 3 legend reports recordings from 8 WT and 11 HET organoids at Day 75, while the MEA Methods describe recordings from four healthy organoids at that age.

  • Lipidomics sample volume differs between figure and Methods

    Minor

    The Fig. 5 legend defines each analyzed sample as 1 mL of conditioned medium, but the lipidomics Methods say 2 mL was transferred for analysis.

3 of 3

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1080/21655979.2021.2005932

    Major

    The cited work was retracted on 2024-02-20 (notice 10.1080/21655979.2024.2299617), before this paper was published (2025-04-09). Its authors could have known.

    Cited work 10.1080/21655979.2021.2005932 · retracted 2024-02-20 · notice 10.1080/21655979.2024.2299617 · this paper published 2025-04-09

1 of 1

Citations

Cites

1 retracted

Flagged first, then by citations

Cited by

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Related

Metadata

Authors
Acosta Ingram, D., Turkes, E., Kim, T. Y., Vo, S., Sweeney, N., Bonte, M.-A., Rutherford, R., Julian, D. L., Pan, M., Marsh, J., Argouarch, A. R., Wu, M., Scharre, D. W., Bell, E. H., Honig, L. S., Vonsattel, J. P., Serrano, G. E., Beach, T. G., Karch, C. M., Kao, A. W., Hester, M. E., Han, X., & Fu, H.
Affiliations
  • UK Dementia Research Institute (GB)
  • The Ohio State University (US)
  • Abigail Wexner Research Institute (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Washington University in St. Louis (US)
  • University of California, San Francisco (US)
  • Columbia University Irving Medical Center (US)
  • Banner Sun Health Research Institute (US)
Corresponding author
Fu, Hongjun
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-04-09
Volume
16
Issue
1
Pages
3312-3312
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-58585-w
PMC
PMC11982250
OpenAlex
W4409279324
Cited by
12
References
130
Citations by year
2026: 10 · 2025: 2
FWCI
3.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • BrightFocus Foundation (A2021027S)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01-AG075092-01, P50 AG023501, AG066444, P30 AG019610, P30AG072980, P30 AG044271)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS110890, U24 NS072026)
  • The Pilot award (H.F.) from The Ohio State University Chronic Brain Injury Discovery Theme, and The Ohio State University Neurological Research Institute Seed grant
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
lipid homeostasis, autophagic flux, tau hyperphosphorylation, frontotemporal lobar degeneration, Alzheimer's disease, free cholesterol, lipid droplets, CDK5R1, PI3K/Akt signaling, p62, iPSC-derived neurons
MeSH terms
Alzheimer Disease, Animals, Autophagy, Cholesterol, Female, Homeostasis, Humans, Male, Mice, Transgenic, Neurons, Phosphorylation, tau Proteins, Lipid Metabolism, Mice, Induced Pluripotent Stem Cells, Frontotemporal Lobar Degeneration, Lipid Droplets

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.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (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.

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