The DOI matches its Crossref record; 113 of the 113 references it cites were found in a registry or an index; 49 of the 61 sources its claims cite were checked for support.
ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids
Open accessAbstract
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
Overview
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Written from the paper’s full text.
TL;DR
Human iPSC-derived cerebral organoids carrying the tau-V337M MAPT mutation show early ELAVL4 upregulation, glutamatergic/synaptic pathway changes, stress granules, splicing dysregulation, and autophagy-lysosomal dysfunction before later tau/P-tau accumulation and selective glutamatergic neuron loss. Glutamate-induced death of mutant neurons is rescued by PIKFYVE inhibition with apilimod or PIKFYVE ASO.
Key findings
- At 2 months, tau-V337M organoids show upregulated MAPT, glutamatergic signaling pathways, and ELAVL4, plus increased stress granules; by 6 months they show selective loss of excitatory neurons in deep-layer (ExDp2, p = 0.004), maturing (ExM, p = 0.003), and newborn (ExN, p = 0.0001) categories, with no effect on interneurons or astrocytes.
- Splicing dysregulation increases from 190 differentially spliced junctions at 2 months to over 5,000 at 6 months; tau and P-tau S396/total tau ratio increase between 4 and 6 months, while LAMP1 and CTSD are increased at 2 months and p62 and LC3-II are reduced at 6 months.
- ELAVL4 binds MAPT RNA and co-localizes with tau and stress granule markers TIA1/G3BP1; over 50% of differentially spliced genes at later time points overlap with neuronal ELAVL-bound RNA.
- Repeated 5 mM glutamate triggers more rapid loss of tau-V337M neurons than isogenic controls (p < 0.0001); apilimod fully rescues this death (p < 0.0001), and PIKFYVE ASO improves survival in mutant (p < 0.0001) but not control neurons (p = 0.5369).
Methods
- Human iPSC lines from three tau-V337M donors and isogenic CRISPR-corrected controls (seven lines total) were differentiated into cerebral organoids and assessed at 2, 4, and 6 months.
- Bulk RNA-seq was performed on 239 organoids (V337M n = 99, V337V n = 140); cell-hashing scRNA-seq was performed on 339 organoids, yielding 379,064 cells (V337M n = 161,706, V337V n = 217,358).
- Analyses included SingleR annotation, Seurat/SCTransform, UMAP, Monocle3 pseudotime, GSEA/IPA, LeafCutter splicing, nELAVL RIP-seq intersection, pseudobulk network analysis, IHC/immunoblot/EM, and longitudinal Synapsin1::GFP neuron survival with glutamate, apilimod, or PIKFYVE ASO.
Limitations
- Stated: low 4R tau expression in the organoid model may miss effects of mutant 4R protein; generalizability to other MAPT mutations and sporadic tauopathies is unknown; microglia are not included; glutamatergic signaling findings require comprehensive electrophysiological validation; and the relative contribution of the identified changes remains to be determined.
- Evident from the text: organoid models do not accurately reflect adult aging, and variability between lines and individual organoids increased over time, indicating donor and clonal effects on long-term maturation.
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Claims the paper makes
44 Own result · 24 Own interpretation · 18 Partly supported · 13 Own method · 11 Supported · 1 Mixed support · 1 Couldn’t confirm · 1 No full text of the sources · 1 No basis given · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Despite this limitation, iPSC-based models derived from individuals with a MAPT mutation indicate molecular mechanisms underlying tauopathies (Gonzalez et al., 2018; lovino et al., 2015; Jiang et al., 2018; Nakamura et al., 2019; Silva et al., 2016, 2020; Wray, 2017).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Disputedcites Gonzalez et al., 2018 sourceExperimental — accuracy not yet measured
The Results identify the patient-derived iPSC model as familial Alzheimer’s disease with a presenilin 1 mutation and Down syndrome, not a MAPT mutation. The Discussion explicitly says tau developed a pathological phenotype in these organoids “without any mutations in the tau gene.” No page number is available in our copy. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Not matchedcites lovino et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Jiang et al., 2018 source
The Results section describes iPSC-derived neurons from MAPT p.R406W carriers used to identify genes and pathways involved in FTLD-tau. The Discussion says the model captures disease mechanisms relevant to other primary tauopathies, supporting the citing sentence’s broad claim. (LLM, conf=0.92)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“Organoid development followed the expected temporal changes (Lancaster et al., 2013; Velasco et al., 2019; Watanabe et al., 2017; Yoon et al., 2019; Figures 1B–1D; Figure S1A).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
What the sources say
- Supportedcites Lancaster et al., 2013 source
The Results section, “Cerebral organoids display discrete brain regions” (page not provided), reports that pluripotency markers diminished while neural-identity markers increased during differentiation. It also reports that forebrain markers remained highly expressed while hindbrain markers decreased as development proceeded, resembling human brain development. (LLM, conf=0.91)
- Supportedcites Velasco et al., 2019 source
The paper states that additional cell types developed in the organoids while “respecting endogenous temporal sequences.” It also reports that the ordering of cell types approximated in vivo human development (passages 1–2; page not provided). (LLM, conf=0.93)
- Supportedcites Watanabe et al., 2017 source
The Results section, “Establishment of efficient and reproducible methods for generating cerebral organoids,” describes successive developmental features at weeks 1, 5, and 8, with later organoids resembling the gestational-week-14 fetal cortex. The Results section on transcriptomic analyses also reports that the transition from week 5 to week 14 organoids closely matched a transition in human fetal cortical development. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This is important because little 4R tau is expressed in induced pluripotent stem cell (iPSC)-derived models without a splice-site mutation (lovino et al., 2015; Sato et al., 2018; Sposito et al., 2015; Verheyen et al., 2018).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Not matchedcites lovino et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Sato et al., 2018 source
The Results section reports that iPSC-derived cortical neurons from cognitively normal controls had very low 4R tau abundance. The Discussion specifies that these neurons expressed approximately 100-fold less 4R than 3R tau. The paper does not explicitly report splice-site genotyping, but its normal-control model supports the point for the models studied. (LLM, conf=0.88)
- Partly supportedcites Sposito et al., 2015 sourceExperimental — accuracy not yet measured
The Results section reports no detectable 4R tau mRNA in control iPSC-derived cortical neurons through 100 days of differentiation, supporting the claim for those cultures. But the Results section on extended culture reports robust 4R expression in control neurons at 365 days, so the unqualified statement does not hold across all culture durations. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
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- Not matched
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In the paper
“The increased tau burden with age mirrors prior observations in 2D iPSC-derived neuronal models (Ehrlich et al., 2015; Fong et al., 2013; lovino et al., 2015; Silva et al., 2016, 2020; Wren et al., 2015) and in the human V337M brain (Spillantini et al., 1996; Spina et al., 2017).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > V337M organoids exhibit increased tau and P-tau and degeneration of vulnerable cortical layers
What the sources say
- Partly supportedcites Ehrlich et al., 2015 sourceExperimental — accuracy not yet measured
The Results section, “Altered Expression of TAU in FTDP-17 iPSC-Derived Neurons” (page unavailable), reports increased tau fragments and increased AT8-positive phosphorylated tau in V337M non-dopaminergic iPSC-derived neurons compared with controls. It does not report that tau burden increased as the neurons aged. Ehrlich et al. is cited for the 2D neuronal-model comparison, not for the separate claim about the human V337M brain. (LLM, conf=0.86)
- Partly supportedcites Fong et al., 2013 sourceExperimental — accuracy not yet measured
The Results section reports increased phosphorylated tau accumulation in 2D iPSC-derived neurons carrying MAPT A152T. It describes an increase with mutation gene dose, not with age, and does not study V337M. The human V337M brain observation is attributed to other citations in the citing sentence. (LLM, conf=0.88)
- Not matchedcites lovino et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“improves proteostasis in neurons (Shi et al., 2018; Staats et al., 2019).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Shi et al., 2018 sourceExperimental — accuracy not yet measured
In “Small molecule and genetic regulators of endosomal trafficking rescue patient iMN survival” (page unavailable), the paper reports that PIKFYVE inhibition lowers glutamate-receptor levels and improves survival in C9ORF72 patient motor neurons. It proposes that increased autophagosome–lysosome fusion may help remove dipeptide repeat proteins, but does not establish a general improvement in neuronal proteostasis. (LLM, conf=0.84)
- Partly supportedcites Staats et al., 2019 sourceExperimental — accuracy not yet measured
The Main text reports that PIKFYVE inhibition reduced dipeptide-repeat protein aggregates in hippocampal neurons of C9ORF72 mouse models and increased lysosome numbers in C9ORF72-deficient hippocampal neurons. These findings support improved handling of disease-associated proteins, but the paper does not establish a general improvement in neuronal proteostasis beyond those models. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“ELAVL4 is selectively expressed in neuronal populations vulnerable to cell death in tau-V337M organoids, consistent with its reported expression in the brain (Bronicki and Jasmin, 2013; DeBoer et al., 2014).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Supportedcites Bronicki and Jasmin, 2013 source
The citation supports the sentence’s background point about ELAVL4 expression in the brain, not the citing authors’ observation about tau-V337M organoids. The “Temporal and Spatial Expression of HuD” section (page unavailable) says HuD/ELAVL4 expression in the adult rodent nervous system is mostly restricted to specific neuronal populations. (LLM, conf=0.90)
- Supportedcites DeBoer et al., 2014 source
The citation is attached to the comparison with reported brain expression, not to the citing authors’ finding about tau-V337M organoids. In “HuD is expressed in mature hippocampal and cortical glutamatergic neurons” (page unavailable), DeBoer et al. report selective HuD expression in lower-layer neocortical neurons and expression in hippocampal neurons. The paper does not test organoids or vulnerability to cell death, but those are not the findings attributed to it here. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“co-localizes with FUS in cytoplasmic speckles and stress granules”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Fallini et al., 2012 sourceExperimental — accuracy not yet measured
The Discussion states that HuD and a pathogenic FUS variant have both been shown to be components of stress granules. It does not establish that they co-localize with each other there or in cytoplasmic speckles; the paper’s co-localization findings concern HuD and TDP-43. (LLM, conf=0.86)
- Partly supportedcites De Santis et al., 2019 sourceExperimental — accuracy not yet measured
The Results section reports ELAVL4 co-localizing with mutant FUS in cytoplasmic speckles in HeLa cells overexpressing both proteins. It also reports co-localization in stress granules in mutant-FUS motor neurons after oxidative stress. The claim omits those conditions and could be read as applying to FUS generally; the paper says wild-type FUS remained nuclear in the stressed motor neurons. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“apilimod has shown good tolerability in phase I and II clinical trials (Ikonomov et al., 2011; Sands et al., 2010)”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Could not verifycites Ikonomov et al., 2011 sourceExperimental — accuracy not yet measured
The Experimental Procedures describe mouse embryos, fibroblasts, and the inhibitor YM201636, but do not address apilimod’s clinical tolerability. Searches for apilimod, phase I and II trials, and tolerability found no relevant passage in our copy. (LLM, conf=0.75)
- Not checked — no full text of the sourcecites Sands et al., 2010 source
plain- Asserted: passes — The authors put it forward as true.
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- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, there was no effect on interneuron or astrocyte numbers (Figure S2C).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 35
- It may state two separate claims as one. 23
Every source the paper cites for this claim was checked and supports it.
In the paper
“In iPSC-derived induced neurons, tau-V337M disrupts neuronal activity regulation and excitability (Sohn et al., 2019), spurring further studies in more complex models.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Supportedcites Sohn et al., 2019 source
The Results sections on AIS plasticity and homeostatic control of neuronal excitability report that tau-V337M impairs activity-dependent AIS plasticity and alters activity patterns in human iPSC-derived neurons. The Discussion likewise states that the mutation disrupts homeostatic AIS rearrangement and leads to neuronal dysfunction. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“FTD-tau is associated with glutamatergic neuronal loss in frontal and temporal cortices (Benussi et al., 2019).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
What the sources say
- Partly supportedcites Benussi et al., 2019 sourceExperimental — accuracy not yet measured
The Abstract reports depletion of glutamatergic pyramidal neurons in the frontal and temporal cortices of patients with FTD. It does not specify that this finding applies to FTD-tau; the Introduction identifies tau as one of several FTD pathologies. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Increasing evidence showing that early alterations in brain development contribute to later manifestation of neurodegenerative diseases (Faravelli et al., 2020) further encourages use of iPSC-based organoid systems to study FTD-tau.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Supportedcites Faravelli et al., 2020 source
The Introduction states that premature alterations during brain development have been related to late manifestations of neurodegenerative disease. The Conclusions further explain how mutations could disrupt neural progenitor maturation and increase vulnerability to later triggers, supporting the claim's qualified account of contribution. (LLM, conf=0.92)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Pathologic studies reveal accumulation of filamentous, hyperphosphorylated tau protein (P-tau) in cerebral cortical and hippocampal neurons and glia, and tau redistribution from axons to the somatodendritic compartment.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Supportedcites Bodea et al., 2016 source
The ‘Tau phosphorylation and neurofibrillary tangle formation’ section describes hyperphosphorylated tau deposits that form filaments and reports tau inclusions in glia. ‘Spreading of tau pathology’ places inclusions in the hippocampus and neocortex, while the Figure 3 caption in ‘Conclusions and perspectives’ contrasts tau’s normal axonal concentration with its pathological accumulation in the neuronal soma and dendrites. Pages are not specified in our copy. (LLM, conf=0.88)
- Could not verifycites Clare et al., 2010 sourceExperimental — accuracy not yet measured
The 'Synaptic Proteins and AD' section mentions neurons containing neurofibrillary tangles, but does not identify their composition or describe tau pathology. Searches for hyperphosphorylated tau and its redistribution from axons to the somatodendritic compartment found no passage addressing the claim in our copy; page numbers were unavailable. (LLM, conf=0.72)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Brain organoids derived from iPSCs develop in culture along a trajectory mimicking key features of fetal brain development and can be patterned toward specific brain regions affected in tauopathy (Camp et al., 2015; Lancaster et al., 2017; Paşca et al., 2015; Velasco et al., 2019; Yoon et al., 2019).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites Camp et al., 2015 source
- Partly supportedcites Lancaster et al., 2017 sourceExperimental — accuracy not yet measured
The Online Methods (Preparation of EBs and enCORs) include an iPS cell line, and the main text reports that engineered organoids form forebrain tissue, including regions consistent with hippocampal identity. It also finds that 60-day organoids most closely match early-gestation human forebrain gene expression. The copy does not establish a developmental trajectory matching fetal brain development or connect the patterned regions to tauopathy. (LLM, conf=0.86)
- Not matchedcites Paşca et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These changes correlate with degeneration of synapses and neuronal loss in frontal and temporal cortices (Bodea et al., 2016; Clare et al., 2010).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Partly supportedcites Bodea et al., 2016 sourceExperimental — accuracy not yet measured
The section ‘Role of tau in dendritic spines and synaptic impairment’ links pathological tau to synaptic degeneration and reports neuronal loss in a tau mouse model. The paper also describes frontal and temporal cortical atrophy in FTLD, but it does not establish that the tau changes correlate with both synaptic degeneration and neuronal loss specifically in those cortices. The mouse-model comparison distinguishes tau changes associated with synaptic loss from those associated with neuronal loss. (LLM, conf=0.85)
- Partly supportedcites Clare et al., 2010 sourceExperimental — accuracy not yet measured
The ‘Synaptic Proteins and AD’ section reports a correlation between synapse loss and neurons containing neurofibrillary tangles, but also notes that another synaptic marker showed no correlation with tangle density. The FTLD section reports synaptic reductions in frontal and temporal regions. Neither section establishes that tau changes correlate with neuronal loss in those cortices. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The tau-V337M mutation selected for this study is located in MAPT exon 12, expressed in iPSC-derived neurons, and associated with FTD with abundant neurofibrillary tangles in frontal and temporal cortices and the cingulate gyrus and atrophy throughout the hippocampus and amygdala (Spillantini et al., 1996; Spina et al., 2017; Sumi et al., 1992).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites Spillantini et al., 1996 source
- Partly supportedcites Spina et al., 2017 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites Sumi et al., 1992 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Disruption of the autophagy-lysosomal pathway (ALP) is another pathological hallmark in human tauopathy brain (Bain et al., 2019; Piras et al., 2016; Wang et al., 2009).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Early autophagy-lysosomal pathway dysfunction in tau-V337M organoids
What the sources say
- Partly supportedcites Bain et al., 2019 sourceExperimental — accuracy not yet measured
The Discussion reports lower LAMP-1 levels in human FTLD-tau cases and suggests that deficient lysosomes or defective vesicular transport may impair tau clearance. This supports disruption of the pathway in the FTLD-tau cases studied, but the paper does not establish it as a pathological hallmark across human tauopathies; its mechanistic conclusion is hedged. (LLM, conf=0.84)
- Supportedcites Piras et al., 2016 source
The Discussion reports abnormal accumulation of autophagy-lysosomal markers as a common feature of the tauopathies studied. The Conclusions likewise state that the autophagosomal-lysosomal clearance pathway is compromised in all three, supporting the citing sentence’s broad paraphrase. (LLM, conf=0.92)
- Partly supportedcites Wang et al., 2009 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) states that the autophagy–lysosomal system is disturbed in Alzheimer disease brain, and the Introduction says lysosomal alterations in Alzheimer disease are well established. The paper does not establish that this disruption is a pathological hallmark across human tauopathies; its own tauopathy experiments use a cell model. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“glutamate levels, and neuronal excitability (Ince-Dunn et al., 2012; Jung and Lee, 2021)”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Ince-Dunn et al., 2012 sourceExperimental — accuracy not yet measured
The Results section, “A new role for nElavl in regulating glutamate in the brain” (page not provided), reports reduced glutamate in mice lacking both Elavl3 and Elavl4. The Results section, “Seizures in Elavl3-/- Mice” (page not provided), links abnormal cortical activity to loss of Elavl3. These findings support a role for the neuronal Elav-like proteins collectively, but do not establish that ELAVL4 alone regulates both glutamate levels and neuronal excitability. (LLM, conf=0.86)
- Partly supportedcites Jung and Lee, 2021 sourceExperimental — accuracy not yet measured
The Introduction identifies HuD as ELAVL4. Section 4.1 reports that mice lacking neuronal ELAV proteins had impaired splicing of genes regulating cellular glutamate levels and spontaneous epileptic seizures. That supports a link to glutamate regulation and excitability, but the passage concerns the neuronal ELAV group, not ELAVL4 individually. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ELAVL4 expression decreases self-renewal of neural progenitor cells and promotes deep-layer glutamatergic neuronal differentiation (Akamatsu et al., 2005; DeBoer et al., 2014; Popovitchenko et al., 2020).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Akamatsu et al., 2005 sourceExperimental — accuracy not yet measured
The Results (page not provided) show increased self-renewal and reduced neuronal differentiation in neural stem/progenitor cells from HuD-deficient mice, supporting a role for HuD in limiting self-renewal and promoting neuronal differentiation. The paper does not establish that the neurons are specifically deep-layer or glutamatergic, and it tests HuD loss rather than experimentally increasing its expression. (LLM, conf=0.88)
- Partly supportedcites DeBoer et al., 2014 sourceExperimental — accuracy not yet measured
The Results section, “HuD is critical for the balanced expression of Tle4 in lower layer neocortical neurons” (page unavailable), reports fewer Tle4-positive lower-layer neurons after HuD deletion and suggests a role in their specification and/or maintenance. That supports a connection to deep-layer neuronal identity, but does not establish that ELAVL4 expression promotes differentiation specifically. Our copy does not report that ELAVL4 decreases neural progenitor self-renewal. (LLM, conf=0.86)
- Partly supportedcites Popovitchenko et al., 2020 sourceExperimental — accuracy not yet measured
The Results section, “Elavl4-v3 promotes lower layer (LL) identity when not repressed in RG” (page unavailable), reports that premature Elavl4-v3 expression in radial glia increased a lower-layer neuronal identity marker, supporting the differentiation part of the claim. It does not establish that ELAVL4 expression decreases neural progenitor self-renewal; the Results section, “Celf1 regulates the balance of glutamatergic neurons” (page unavailable), instead reports greater progenitor retention in a condition with increased Elavl4 protein. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“binds to the glutamatergic receptor GRM5 and other genes within the long-term potentiation (LTP) pathway (Bolognani et al., 2010)”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Supportedcites Bolognani et al., 2010 source
The Results (Gene ontology analysis of HuD targets; page unavailable) state that the long-term potentiation pathway contains a number of HuD targets. The Discussion (page unavailable) identifies metabotropic glutamate receptor 5 (mGluR5, encoded by GRM5) as another HuD target and names other targets involved in long-term potentiation. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ELAVL4 is a target of FUS activity”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Could not verifycites Fallini et al., 2012 sourceExperimental — accuracy not yet measured
The Discussion describes FUS as a regulator of neuronal mRNA transport and stability, and separately discusses HuD and other ELAV-family proteins in relation to TDP-43 aggregates. Searches for ELAVL4 as a FUS target and for FUS regulation of HuD found no passage connecting them in our copy. (LLM, conf=0.75)
- Supportedcites De Santis et al., 2019 source
The Results section, “FUS Regulates ELAVL4 Expression by Binding the 3′ UTR of Its mRNA,” identifies ELAVL4 as a target of FUS regulation. It reports increased ELAVL4 expression in FUS-mutant motor neurons and increased ELAVL4 3′ UTR reporter activity in the presence of mutant FUS; the demonstrated effect is chiefly for mutant FUS. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“tau-TIA1 interaction can lead to formation and stabilization of toxic tau oligomers (Ash et al., 2021).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Supportedcites Ash et al., 2021 source
The Results section reports that adding TIA1 and RNA increases formation of tau oligomers, and that the resulting oligomeric tau is neurotoxic. The Discussion says TIA1 inhibits conversion of oligomers into fibrils, promoting their accumulation—supporting the claim that the interaction helps form and stabilize toxic oligomers. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ELAVL4 binds the 3′ UTR of MAPT RNA in rat primary neurons and in mouse P19 cells”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Atlas et al., 2007 source
- Not checked — no full text of the sourcecites Behar et al., 1995 source
- Partly supportedcites Jung and Lee, 2021 sourceExperimental — accuracy not yet measured
The Introduction identifies HuD as ELAVL4, and §3.1 says HuD regulates tau expression. A reference listed in the paper concerns tau mRNA and HuD protein in differentiated P19 neuronal cells, but our copy does not establish direct binding to the MAPT 3′ UTR in either P19 cells or rat primary neurons. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“ELAVL4 regulates RNA splicing (Scheckel et al., 2016)”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Scheckel et al., 2016 sourceExperimental — accuracy not yet measured
The Results section, “nELAVL regulates splicing of human brain targets” (page unavailable), reports altered exon splicing after nELAVL depletion. But the depletion targeted ELAVL2, ELAVL3, and ELAVL4 together, as specified in “nELAVL proteins regulate mRNA abundance of human brain targets” (page unavailable). The paper therefore supports a role for the neuronal ELAVL proteins in splicing, not an independently established role for ELAVL4 alone. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“is present in TAR DNA-binding protein 43 (TDP-43) inclusions (Fallini et al., 2012; De Santis et al., 2019).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Supportedcites Fallini et al., 2012 source
Figure 7 reports that HuD co-aggregated with TDP-43 C-terminal-fragment-positive cytoplasmic inclusions in transfected primary motor neurons. The Discussion says it remains unknown whether HuD is present in pathological aggregates in animal models or ALS patients; the cited finding concerns experimentally induced inclusions. (LLM, conf=0.88)
- Supportedcites De Santis et al., 2019 source
The Results section, “ELAVL4 Is a Component of Pathological Inclusions in ALS Patients’ Specimens,” reports ELAVL4 in phosphorylated TDP-43-positive cytoplasmic inclusions in sporadic ALS specimens. The Figure 6 caption likewise identifies inclusions positive for both pTDP-43 and ELAVL4. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Tau influences stress granule formation in neurons”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Ash et al., 2021 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says tau selectively associates with TIA1-containing stress granules. The paper examines TIA1’s effects on tau phase separation and tests tau toxicity in cultured neurons, but the passages do not show that tau influences stress granule formation in neurons. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PIKFYVE inhibition increases the number of EEA1-positive endosomes and LAMP1-positive lysosomes”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Shi et al., 2018 sourceExperimental — accuracy not yet measured
The section on small-molecule regulators of endosomal trafficking (page not provided) reports that PIKFYVE inhibition increased the size of EEA1-positive endosomes, not their number. The lysosomal-biogenesis section attributes restored numbers of LAMP1-positive lysosomes to forced C9ORF72 expression; our copy does not report that PIKFYVE inhibition increased their number. (LLM, conf=0.88)
- Supportedcites Staats et al., 2019 source
The Main text reports that apilimod, a PIKFYVE inhibitor, increased EEA1-positive vesicles in hippocampal neurons and astrocytes of C9orf72-deficient mice. It also reports increased LAMP1-positive vesicles in hippocampal neurons after treatment. The claim omits that experimental setting but accurately summarizes the reported effects. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“humans and mice haplodeficient for PIKFYVE are normal”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
What the sources say
- Partly supportedcites Ikonomov et al., 2011 sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that heterozygous PIKfyve WT/KO mice developed without ostensible defects. But the Discussion (page unavailable) says humans with heterozygous PIKFYVE mutations can have fleck corneal dystrophy, a pathology not seen in the mice. The claim that affected humans are normal is therefore not supported. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites Sands et al., 2010 source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It would be of interest to include microglia in the model, given their contribution to tau pathology, spread, and synaptic degeneration (Vogels et al., 2019).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION > Limitations of the study
What the sources say
- Supportedcites Vogels et al., 2019 source
The section on the effects of tau pathology on microglia says dysfunctional glial cells can contribute to neuronal tau pathology. The introduction identifies microglial involvement in tau-induced synapse loss and tau spreading, and the section on synaptic spreading describes reduced tau spread after microglial depletion. No page numbers are provided in our copy. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The false discovery rate (FDR) of the differential expression test was estimated using the Benjamini-Hochberg (BH) method (Reiner et al., 2003).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
What the sources say
- Supportedcites Reiner et al., 2003 source
The section “The linear step-up procedure (BH)” describes BH as a procedure for controlling FDR. “Resampling FDR adjustments” explains how the paper obtains a BH point estimate, and “Results of multiple testing on the original data” reports using that estimator for differential-expression tests. The citation supports identifying BH as the method, though it does not verify what the citing authors did in their own analysis. (LLM, conf=0.90)
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Data from different sequencing runs, batches and ages were integrated and scaled using SCTransform (Hafemeister and Satija, 2019), while regressing out the following covariates; percentage of mitochondrial genes, the number of cells collected per parent organoid, the number of genes per cell and the number of reads per cell.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
What the sources say
- Supportedcites Hafemeister and Satija, 2019 source
The Discussion identifies sctransform as the authors’ method for normalization and variance stabilization and says its model can include covariates such as mitochondrial percentage and experimental batch. The citation identifies the method used; the particular runs, ages, organoids, and covariates listed in the citing sentence describe the citing authors’ own analysis, not results attributed to this paper. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Differential gene expression between MAPT mutation organoids and isogenic controls was predicted by linear mixed model analysis using the variancePartition package (v1.14.1) in the R programming environment (Hoffman and Roussos, 2021) to account for sample correlations within isogenic lines and differentiation batches.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
What the sources say
- Supportedcites Hoffman and Roussos, 2021 source
The Software section identifies dream as a function in the variancePartition package. The Dream model section describes differential-expression analysis using a linear mixed model with multiple random effects, which supports citing it as the method used to account for sample correlations. The MAPT organoid analysis is the citing authors’ application, not a result attributed to this source. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overtime, the proportion of upper cortical layer-enriched (ExM-U) neurons increased, as did inhibitory neurons, astrocytes, and oligodendrocytes (all p < 2.2 × 10−16; Figures 1B–1D).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These differences were validated by immunohistochemistry (IHC) analysis, which showed a reduction in neuronal nuclear protein+ (NeuN+) neurons at 4 and 6 months (Figures 2B and 2C) and in MAP2+ neurons at 6 months (Figures S2A and S2B).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lysosome-related multi-membrane lamellar bodies were rare in healthy neurons (Figure 2E) but more frequent in tau-V337M neurons, including those showing early signs of apoptosis (Figure 2F), suggesting ALP dysfunction.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Early autophagy-lysosomal pathway dysfunction in tau-V337M organoids
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, pro-CTSD was increased significantly at 6 months in the absence of increased active CTSD, whereas sequestosome 1 (p62) and microtubule-associated protein 1A/1B-light chain 3 (LC3-II) were reduced significantly at the same time point (Figures 2H and 2I), suggesting defects in proteolytic cleavage and activity.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Early autophagy-lysosomal pathway dysfunction in tau-V337M organoids
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tau-V337M organoids showed no genotype-dependent differences at 2 months (Figure 2J), but a significant increase in total tau and the P-tau S396/total tau ratio emerged between 4 and 6 months compared with isogenic controls (Figures 2J–2L).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > V337M organoids exhibit increased tau and P-tau and degeneration of vulnerable cortical layers
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Figure 7K: nisogenic+nc = 120, nisogenic+ASO = 120, Chi-sq = 0.3814, p = 0.5369.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 120- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“for Figures 7B: nisogenic = 80, nmutant = 80, Chi-sq = 3.723, p = 0.0537;”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 80- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no batch-specific effect on differentiation over three replicates assessed by uniform manifold approximation and projection (UMAP) (Figure S1B) and no clustering because of mutation at 2 or 4 months (Figure S1C).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Transcriptional signatures in the human frontal cortex at this age correlate highly with gene expression profiles of organoids (Qian et al., 2016).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
What the sources say
- Not checked — no full text of the sourcecites Qian et al., 2016 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, PIKFYVE inhibition may rescue glutamate-induced neurodegeneration by correcting ALP dysfunction, increasing turnover of misfolded tau, and favoring elimination of internalized NMDA and AMPA receptors over recycling back to the synapse.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings demonstrate that iPSC-tau-V337M organoids phenocopy aspects of ALP dysfunction seen in the FTD brain, which may be triggered by expression of mutant tau protein in neurons early in disease development.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Early autophagy-lysosomal pathway dysfunction in tau-V337M organoids
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“High-molecular-weight (HMW) ubiquitinated species were increased significantly in tau-V337M organoids at 2 months, suggesting disrupted degradation and accumulation of poly-ubiquitinated proteins and, thus, increased proteostasis stress in mutant organoids.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Early autophagy-lysosomal pathway dysfunction in tau-V337M organoids
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, dysfunctional proteostasis may result in increased levels of tau and ELAVL4 because of impaired protein clearance, promoting their cytosolic accumulation.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given its pleiotropic functions, our observation of perturbed ELAVL4 expression and localization could contribute to several phenotypes observed in tau-V337M organoids, including aberrant MAPT/tau expression, early neuronal maturation, aberrant glutamate signaling, and dysregulated splicing.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All presented differential expression, GSEA, pathway enrichment and splicing analyses p values were adjusted for multiple test correction.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 239- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Two organoids were excluded from further analysis due to inconsistent positioning away from the remaining samples by principal components analysis”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 2- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the low 4R tau expression in these organoid models, additional effects of the mutant 4R protein may be missed.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION > Limitations of the study
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: The organoid models have low 4R tau expression.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The resulting dataset for analysis included 379,064 cells (V337M n = 161,706, V337V n = 217,358).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 348- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Protein bands’ densitometry (pixel mean intensity in arbitrary units, a.u.) was measured with ImageJ and normalized to the respective internal control (GAPDH) band.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data was also corrected for differentiation batch.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“resulting in a final dataset consisting of 239 organoids (V337M n = 99, V337V n = 140).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 239- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our working model, the MAPT mutation results in accumulation of mutant tau”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All reported p values were adjusted for multiple test correction; Significance was defined as adjusted p < 0.05.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For every set of slides stained, a neuropathologically confirmed severe AD case and healthy control case was included as a batch control.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Pathological changes assessed using semiquantitative analysis were scored by two researchers (JFC and KW) blinded to mutational and control conditions using a semiquantitative scoring system”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“of which 339 passed quality control, determined by samples containing detectable cells with clear HTO identities.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plainn = 339- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data characterizing glutamatergic signaling in tau-V337M organoids require additional validation by comprehensive electrophysiological assessment to confirm our hypothesized mechanism.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION > Limitations of the study
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although these changes are initially accommodated by plasticity, over time they result in glutamatergic neuron death.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Band intensity was analyzed using GeneTools, normalized against total protein by Ponceau S staining of each blot, and band intensity was expressed relative to the normalized control within each blot.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and second by impaired proteostasis, preventing recycling of receptors away from the synapse and promoting further tau accumulation.”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The authors state this as an assumption.
Organoid models do not accurately reflect adult aging.
“Given that organoid models do not accurately reflect adult aging, it is interesting that we observed neurodegeneration.”
The paper relies on this without support.
MAPT is alternatively spliced into 3R and 4R tau isoforms by exclusion or inclusion of exon 10.
“MAPT is alternatively spliced, resulting in two major isoforms, 3R and 4R tau, defined by exclusion or inclusion of exon 10, respectively.”
The paper relies on this without support.
Temporal analysis of human organoid models has revealed early pathological events in neurodegeneration.
“Temporal analysis of human organoid models has revealed early pathological events in neurodegeneration.”
The paper relies on this without support.
The organoid models have low 4R tau expression.
“Given the low 4R tau expression in these organoid models”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Overall, our data suggest HNOs with the MAPT R406W mutation can recapitulate the increased tau phosphorylation observed in vitro, in vivo, and in patient samples of FTLD brains5.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using several experimental models, it has been shown that increased cholesterol levels are present in tandem with neuronal dysfunction and tau aggregation4,5,18–25.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Importantly, our findings of altered lipid profiles and increased tau phosphorylation in HNOs with MAPT mutations coincide with findings from previously published literature using HNO models to study MAPT gene mutations4,5.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“In addition, early dysfunction of glutamatergic neuronal networks is highlighted in previous studies of MAPT V337M HNOs5.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
In the citing paper
“Increased phosphorylation of tau has been observed in HNOs and iPSC-derived neurons with the MAPT mutations5,86.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
In the citing paper
“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.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [5]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“single-cell RNA-seq (scRNA-seq) on 339 individual organoids (>370,000 cells, ~800–1,000 cells per organoid).”
§ ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids > RESULTS > Selective loss of glutamatergic neurons in tau-V337M organoids
Reported 1000 · recomputed 1118.182891
Citations
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
Liao, Y., Smyth, G. K., & Shi, W. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt656 · Cited by 27,219
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174
UMAP: Uniform Manifold Approximation and Projection
McInnes, L., Healy, J., Saul, N., & Großberger, L. (2018) · Journal of Open Source Software · doi:10.21105/joss.00861 · Cited by 9,826
QuPath: Open source software for digital pathology image analysis
Bankhead, P., Loughrey, M. B., Fernández, J. A., Dombrowski, Y., McArt, D. G., Dunne, P. D., McQuaid, S., Gray, R. T., Murray, L. J., Coleman, H. G., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-17204-5 · Cited by 8,908
Trapnell, C., Cacchiarelli, D., Grimsby, J., Pokharel, P., Li, S., Morse, M., Lennon, N. J., Livak, K. J., Mikkelsen, T. S., & Rinn, J. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2859 · Cited by 7,314
UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction
McInnes, L., Healy, J., & Melville, J. (2018) · arXiv · doi:10.48550/arxiv.1802.03426 · Cited by 7,101
Cerebral organoids model human brain development and microcephaly
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., & Knoblich, J. A. (2013) · Nature · doi:10.1038/nature12517 · Cited by 5,372
Reversed graph embedding resolves complex single-cell trajectories
Qiu, X., Mao, Q., Tang, Y., Wang, L., Chawla, R., Pliner, H. A., & Trapnell, C. (2017) · Nature Methods · doi:10.1038/nmeth.4402 · Cited by 5,070
Cited by
Sorted by citations
Solving neurodegeneration: common mechanisms and strategies for new treatments
Wareham, L. K., Liddelow, S. A., Temple, S., Benowitz, L. I., Di Polo, A., Wellington, C., Goldberg, J. L., He, Z., Duan, X., Bu, G., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00524-0 · Cited by 324
Self-citationHuman cerebral organoids — a new tool for clinical neurology research
Eichmüller, O. L., & Knoblich, J. A. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00723-9 · Cited by 319
Zeng, H., Huang, J., Zhou, H., Meilandt, W. J., Dejanovic, B., Zhou, Y., Bohlen, C. J., Lee, S.-H., Ren, J., Liu, A., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01251-x · Cited by 233
Advancing cell therapy for neurodegenerative diseases
Temple, S. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.03.017 · Cited by 221
Self-citationAccelerating Alzheimer’s therapeutic development: The past and future of clinical trials
Boxer, A. L., & Sperling, R. (2023) · Cell · doi:10.1016/j.cell.2023.09.023 · Cited by 197
Metadata
- Authors
- Bowles, K. R., Silva, M. C., Whitney, K., Bertucci, T., Berlind, J. E., Lai, J. D., Garza, J. C., Boles, N. C., Mahali, S., Strang, K. H., Marsh, J. A., Chen, C., Pugh, D. A., Liu, Y., Gordon, R. E., Goderie, S. K., Chowdhury, R., Lotz, S., Lane, K., Crary, J. F., Haggarty, S. J., Karch, C. M., Ichida, J. K., Goate, A. M., & Temple, S.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Harvard University (US)
- Neural Stem Cell Institute (US)
- University of Southern California (US)
- Washington University in St. Louis (US)
- Corresponding author
- Goate, Alison M.
- Temple, Sally
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 184
- Issue
- 17
- Pages
- 4547-4563.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8635409
- OpenAlex
- W3183726003
- Cited by
- 175
- References
- 112
- Citations by year
- 2026: 32 · 2025: 35 · 2024: 37 · 2023: 29 · 2022: 37 · 2021: 5
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (AG046374)
- New York State Stem Cell Science (C029158)
- National Institute of Neurological Disorders and Stroke (R35 NS097277, F31NS117075)
- Harrington Discovery Institute, University Hospitals
- Hope Center for Neurological Disorders
- Eisai
- Rainwater Charitable Foundation
- New York Genome Center (U54NS092089, U01AG045390)
- U.S. Department of Defense (W81XWH-21-1-0168, W81XWH-21-1-0131, W81XWH-20-1-0424)
- National Institute on Aging (R01 AG056293, 2R01NS097850)
- John Douglas French Alzheimer's Foundation
- Biogen
- ALS Association
- Association for Frontotemporal Degeneration
- AbbVie
- BrightFocus Foundation
- Genentech
- Alzheimer's Drug Discovery Foundation
- Denali Therapeutics
- Tau Consortium
- California Institute for Regenerative Medicine
- New York Stem Cell Foundation
- GlaxoSmithKline
- Sächsische Aufbaubank
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- frontotemporal dementia, MAPT mutations, ELAVL4, RNA-binding proteins, alternative splicing, glutamatergic neurons, glutamate excitotoxicity, stress granules, autophagy, tau accumulation, brain organoids, iPSC-derived neurons, apilimod, neurodegeneration
- MeSH terms
- ELAV-Like Protein 4, Stress Granules, Autophagy, Cell Line, Humans, Hydrazones, Lysosomes, Morpholines, Mutation, Neurons, Organoids, Phosphorylation, Pyrimidines, RNA Splicing, Synapses, Signal Transduction, Biomarkers, Up-Regulation, tau Proteins, Cell Death, Glutamic Acid, Body Patterning, Cerebrum
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 2026-10-23, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-23 (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.
What counts as a claim ›How we measure confidence ›How we check this ›
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