The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index; 29 of the 44 sources its claims cite were checked for support.
Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms
Open accessAbstract
APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.
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TL;DR
Overexpressing LDLR in P301S tauopathy mice markedly lowers brain apoE and reduces tau pathology, neurodegeneration, synaptic loss, and microglial activation. The protective effects are linked to apoE-dependent microglial metabolic reprogramming, with additional preservation of myelin and OPC pools.
Key findings
- LDLR overexpression (OX) in P301S mice at 9 months reduced brain atrophy, synaptic loss, and postsynaptic density loss, and shifted p-tau staining toward an early-disease pattern; CSF and soluble brain apoE were reduced by ~90%, and p-tau was significantly reduced in RAB and RIPA fractions, while total human tau was unchanged.
- Microglial LDLR OX cell-autonomously downregulated microglial *Apoe* expression and intracellular apoE, and was associated with suppressed microglial activation; in 20-month mice, LDLR microglia showed reduced “DAM” and proinflammatory gene expression, and P301S/LDLR mice had less CD68+ microglial activation than P301S mice.
- snRNAseq of 31,785 nuclei identified 10 cell clusters; microglial subclustering found a P301S-enriched DAM cluster, a P301S/LDLR-unique cluster, and an apoE-deficiency-associated cluster. ApoE-deficient and LDLR microglia shifted toward catabolism with upregulated lysosomal genes and LGMN, downregulated anabolic/mTOR pathways, and LDLR microglia uniquely upregulated ion channels and neurotransmitter receptors.
- ApoE-deficient and LDLR-overexpressing mice had enlarged OPC pools and greater myelin preservation: OPC cluster representation was ~20% in EKO/P301S/EKO, 10–13% in LDLR/P301S/LDLR, and 3–5% in WT/P301S; P301S/LDLR and P301S/EKO mice also showed less demyelination and lower axonal G-ratio than P301S mice, with less reactive astrocyte activation.
Methods
- LDLR Tg mice were crossed to P301S and apoE KO mice; experiments used male mice except where stated, at ages including 3, 9, 20, and 24 months, with primary microglia, acutely isolated microglia, FACS, qPCR, western blot, ELISA, immunohistochemistry, electron microscopy, and lysosomal enzyme activity assays.
- Single-nuclei RNAseq used 10x Genomics on pooled hippocampi from 7–8 mice per genotype, yielding 31,785 nuclei; Seurat was used for clustering, MAST for differential expression, and Metascape for pathway analysis.
- Statistics used mean ± SEM, normality testing, t-tests or one-way ANOVA with Tukey post hoc, or Mann-Whitney/Kruskal-Wallis with Dunn’s post hoc, with significance thresholds *p*<0.05 to *p*<0.0001.
Limitations
- The paper states that further study is required to carefully address whether LDLR affects pathological tau spreading, and that functional characterization of reactive astrocytes in neurodegeneration needs future studies.
- Evident from the text: snRNAseq pooled 7–8 mice per genotype into a single sample per genotype, limiting animal-level statistical inference for transcriptomic comparisons.
- Evident from the text: male mice were used for all experiments except a few cases where sex was specifically stated, limiting generalization across sexes; the paper also notes that absolute tau and p-tau ELISA values cannot be directly compared because of different standards and antibody-binding capacities.
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Claims the paper makes
84 Own result · 38 Own interpretation · 15 Supported · 8 Own method · 7 Partly supported · 7 No full text of the sources · 4 No basis given · 2 Sources not found · 1 Not supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“ApoE had a strong immunomodulatory function and promoted neurodegeneration and tau pathogenesis predominantly by driving microglial activation (Shi et al., 2019).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Supportedcites Shi et al., 2019 source
The Discussion states that microglial depletion eliminated apoE’s effect on neurodegeneration and abolished its effects on phosphorylated-tau progression in the tauopathy mouse model. It concludes that apoE’s effects on both are primarily mediated through microglial function; the Introduction also describes apoE as a potent immune modulator. (LLM, conf=0.93)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“ApoE ablation in P301S tau transgenic (Tg) mice markedly reduced brain atrophy and tau pathology compared to the presence of apoE, whereas apoE4 significantly exacerbated neurodegeneration compared to apoE2 and apoE3 (Shi et al., 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Partly supportedcites Shi et al., 2017 sourceExperimental — accuracy not yet measured
The paper reports that ApoE knockout largely attenuated brain atrophy in P301S mice expressing human ApoE. It also reports differences in tau pathology across ApoE genotypes, but not a marked overall reduction in tau pathology with knockout: at 9 months, overall p-tau staining differences had decreased, although staining patterns differed. The reported greater neurodegeneration with ApoE4 than with ApoE2 or ApoE3 is supported (main text, passages indexed under Abstract; page unavailable). (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“microglia-derived apoE was shown to cell-autonomously promote microglial activation towards the neurodegenerative “MGnD/DAM” phenotype (Krasemann et al., 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
What the sources say
- Supportedcites Krasemann et al., 2017 source
The Results section reports that deleting Apoe specifically in microglia repressed a disease-associated gene and restored homeostatic genes in phagocytic microglia. The Discussion explicitly describes APOE regulation of the MGnD phenotype as cell-autonomous. Page numbers were not supplied in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“ApoE ablation in P301S tau transgenic (Tg) mice markedly reduced brain atrophy and tau pathology compared to the presence of apoE, whereas apoE4 significantly exacerbated neurodegeneration compared to apoE2 and apoE3 (Shi et al., 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Supportedcites Shi et al., 2017 source
The passage labeled Abstract reports significantly more brain atrophy in nine-month-old P301S/E4 mice than in P301S/E2 and P301S/E3 mice. It identifies this as more severe tau-mediated neurodegeneration with ApoE4. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“Low-density lipoprotein receptor (LDLR) is one of the two primary metabolic receptors (the other is low-density lipoprotein receptor-related protein 1, LRP1) mediating the clearance of apoE lipoproteins (Holtzman et al., 2012; Ishibashi et al., 1994).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Supportedcites Holtzman et al., 2012 source
The section “Evidence that LRP1 and LDLR Are Key Metabolic Receptors for ApoE/Lipoprotein in the Brain” explicitly identifies LDLR and LRP1 as the two primary metabolic receptors for apoE/lipoprotein. It also describes changes in brain apoE levels when LDLR expression is altered, consistent with a role in its clearance. (LLM, conf=0.95)
- Partly supportedcites Ishibashi et al., 1994 sourceExperimental — accuracy not yet measured
The Discussion supports LDLR as one of two receptors involved in apoE-mediated lipoprotein clearance. It cautions, however, that the identity of the second receptor is not known for certain, so the citing sentence’s definite identification of it as LRP1 goes beyond the paper’s conclusion. Page numbers are not given in the supplied passages. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“We and others subsequently identified microglia as the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models (Mancuso et al., 2019; Shi et al., 2019).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Partly supportedcites Mancuso et al., 2019 sourceExperimental — accuracy not yet measured
The Discussion reports that inhibiting microglial proliferation in P301S mice prevented neurodegeneration and potentially slowed tau aggregation. It describes activated microglia as deleterious, but does not establish them as the principal driving force of either process across tauopathy mouse models; it explicitly notes uncertainty about whether their effect on tau pathology is predominant. The indexed passages provide section labels but no page numbers. (LLM, conf=0.86)
- Supportedcites Shi et al., 2019 source
The Discussion states that microglial activation drives neurodegeneration in the studied tauopathy mouse model and that microglia drive progression of phosphorylated-tau pathology. This supports the claim attributed to Shi et al.; the sentence’s plural “models” refers to the studies cited together, while this paper provides evidence from one model. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“LDLR mice also showed a moderate increase in enzyme activities compared to WT mice (Figure 5K)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar differences were also observed in tau Tg mice (Figure 7B, C).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Corresponding to LDLR OX, apoE levels in the CSF of LDLR and P301S/LDLR mice were markedly reduced by ~90% compared to WT and P301S mice respectively (Figure 2A).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the absence of the tau transgene, apoE- and LDLR-associated gene expression changes (WT vs. EKO or WT vs. LDLR) were primarily enriched in neurons, particularly in excitatory neurons.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Among the six astrocyte subclusters, cluster 0 and cluster 1 shrunk drastically in P301S mice (Figure 6A, B)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We confirmed increased density of OPCs in the molecular layer of dentate gyrus (DG) in the hippocampus of 9-month EKO and LDLR Tg mice compared to WT mice by immunofluorescent staining with the OPC marker CSPG4 (Figure 7B, C).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, apoE level had a strong positive correlation with insoluble tau level, and trended toward a negative correlation with soluble tau levels in both P301S and P301S/LDLR mice (Figure 2C).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“cluster 3 was strongly enriched in EKO and P301S/EKO mice (~20%), and to a less extent in LDLR and P301S/LDLR mice (10-13%) compared to WT and P301S mice (3-5%) (Figure 6A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“activated microglia (CD68+) in 9-month P301S mice almost invariably showed large punctate intracellular apoE staining”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This effect was not observed in 3-month old mice (Figure 5N).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we consistently observed Ldlr overexpression in LDLR Tg microglia compared to WT microglia.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“whereas in P301S/LDLR mice, minimal intracellular apoE, or only tiny apoE puncta were observed in activated microglia (Figure 3L).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“microglia isolated from aged (20-month) EKO mice showed a similar reduction of p4EBP compared to microglia from WT mice (Figure 5M).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“LDLR microglia showed a similarly increased level of LGMN compared to WT microglia”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast to no change of total human tau levels, LDLR OX in P301S mice significantly reduced p-tau levels in the RAB and RIPA fractions (Figure 2B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“corresponding to increased Ldlr expression (Figure 3C)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“At 3-months of age, an early time point before activation of DAM microglia (Figure S2A), LDLR OX did not affect early ptau histopathology that is present in the mossy fibers of the hippocampus (type1 ptau, not present in WT mice) (Figure S2B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX does not affect tau pathology and brain volume at an early age prior to microglial activation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Significantly reduced insoluble apoE was also observed in P301S/LDLR mice compared to P301S mice (Figure 2B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Electron microscopy also revealed severe loss of postsynaptic densities (PSDs) in the stratum radiatum of hippocampal CA1 region in P301S mice”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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In the paper
“The proportion of inhibitory neurons, in contrast, was increased in P301S mice compared to other groups (Figure 4C, D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
plaincorrelationaln = 8- Asserted: passes — The authors put it forward as true.
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In the paper
“We verified upregulation of Lgmn in acutely isolated microglia from EKO mice compared to that from WT mice by qPCR (Figure 5H)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
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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In the paper
“a significant reduction of Apoe gene expression (Figure 3C)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Compared to cluster 2, top downregulated pathways in cluster 3 include “myeloid leukocyte activation”, “antigen processing and presentation”, and “myeloid leukocyte differentiation”, all featuring genes involved in microglial activation”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR-associated microglia upregulate genes encoding specific subsets of ion channels and neurotransmitter receptors and downregulate microglial activation pathways
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“no volume differences were observed between P301S and P301S/LDLR mice (Figure S2D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX does not affect tau pathology and brain volume at an early age prior to microglial activation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“in microglia isolated from 20-month mice, LDLR Tg microglia, like EKO microglia, showed significantly reduced “DAM” and proinflammatory gene expression compared to WT microglia”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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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
“The largest group of upregulated genes in cluster 4 encode lysosomal enzymes and proteins involved in cellular degradation, including Lgmn, Ctss, Ctsl, Hexb, Man2b1, Lamp1, Lamp2, Abca2 and others (Figure 5F, G).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
plain- 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.
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
“neurodegeneration-associated gene expression change (P301S vs. WT) mainly occurred in microglia and astrocytes.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
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.
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
“which was significantly attenuated in P301S/LDLR mice (Figure 1C, D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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.
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
“However, in the setting of tauopathy, the highest level of gene expression change shifted from neurons to microglia in both conditions (P301S vs. P301S/EKO, P301S vs. P301S/LDLR)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“P301S/LDLR mice showed no alteration in total human tau levels in any fractions compared to P301S mice (Figure 2B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 addition, apoE levels positively correlated with p-tau levels in all fractions (Figure 2D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“microglia from LDLR Tg mice also overexpressed LDLR, particularly a low molecular weight form of LDLR (Figure 3A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“immunoblotting of acutely isolated microglia from 11-month P301S, P301S/LDLR and P301S/EKO female mice showed reduced phosphorylation of 4EBP (p4EBP) - an mTORC1 effector, in P301S/EKO microglia compared to P301S microglia (Figure 5L)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
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.
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
“However, apoE level had a strong positive correlation with insoluble tau level, and trended toward a negative correlation with soluble tau levels in both P301S and P301S/LDLR mice (Figure 2C).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
hedgedcorrelational- 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.
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
“a similar pattern of p4EBP levels was also observed in P301S/LDLR microglia compared to P301S and P301S/EKO microglia (Figure 5L-N)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
plain- Asserted: passes — The authors put it forward as true.
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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
“We identified two subpopulations of homeostatic microglia (cluster 0 and 1) that were enriched in non-tau Tg mice, but were drastically reduced in P301S mice (Figure 5A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“LDLR microglia showed an intermediate level of p4EBP compared to WT and EKO microglia”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Both LDLR and P301S/LDLR mice showed an ~90% reduction of soluble apoE similar to that seen in the CSF (Figure 2B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Unsupervised clustering yielded six subclusters among all samples (Figure 5A).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
plain- 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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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
“Cluster 4 was specifically associated with apoE deficiency, as it was enriched in apoE-deficient mice, regardless of the presence or absence of tau transgene (Figure 5A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
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.
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
“Here we found that compared to WT mice, P301S mice showed a marked increase of Apoe expression that occurred uniquely in microglia over other cell types (Figure S4A).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Downregulated genes in cluster 4 microglia primarily fell into anabolic pathways, such as “peptide chain elongation” characterized by ribosome protein genes; “glycolysis”, including genes encoding glycolytic enzymes such as Eno2, Gapdh, and Ldha; and “mTOR signaling””
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
plain- 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.
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
“The density of OPCs was increased in P301S mice compared to WT mice”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“which was partially rescued in P301S/LDLR mice (Figure 1E, F).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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.
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
“Synapsin staining revealed a marked synaptic loss in P301S mice compared to WT and LDLR mice, particularly in the stratum lucidum of hippocampal CA3 region”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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.
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
“found increased LGMN protein level in acutely isolated microglia from both young (3-month) and aged (20-month) EKO mice compared to WT mice by western blot (Figure 5I, J).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
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.
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
“We observed significantly increased activity of all three enzymes in EKO mice compared to WT mice (Figure 5K)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
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.
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
“whereas P301S/LDLR mice had significantly less brain volume loss than P301S mice (Figure 1A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the difference of intracellular apoE level between WT and LDLR Tg microglia was increased in aged mice (20-month) compared to young mice (3-month) (Figure 3H, I).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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
“Compared to WT and LDLR mice that had a normal brain volume, P301S mice showed severe brain atrophy in the hippocampus and piriform/entorhinal cortex”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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.
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 pathways highlighted genes encoding ion channels and neurotransmitter receptors, such as voltage-gated K+ and Na+ channels (Kcnc1, Kcnc3, Scn2a, Scn2b), Na+/K+-ATPase (Atp1a1), NMDA receptor (Grin2c), GABA-A receptor (Gabra6), and metabotropic glutamate receptor (Grm4) (Figure S5A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR-associated microglia upregulate genes encoding specific subsets of ion channels and neurotransmitter receptors and downregulate microglial activation pathways
plain- 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.
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
“whereas the astrocyte population remained stable across groups (Figure 4C, D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
plainn = 8- 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.
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
“P301S/LDLR mice showed significantly attenuated microglial activation relative to P301S mice by CD68 staining (Figure 3M).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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
“Cluster 2 was highly enriched in P301S mice (Figure 6A, B)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
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.
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
“as well as a marked reduction of intracellular apoE protein level (Figure 3A, B) was observed in cultured LDLR-overexpressing microglia.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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 the hippocampus, aged LDLR and EKO mice also showed a higher myelin density in the molecular layer compared to WT mice (Figure S6D, E).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“Interestingly, a similar protective effect of apoE-deficiency and LDLR-OX on myelin integrity was also observed in aged mice in the absence of tauopathy.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“Corresponding to increased myelin damage, P301S mice showed marked microglial activation in the corpus callosum (Figure 7H, J)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
plain- 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.
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
“Surprisingly, even in the absence of tau pathology, LDLR and EKO mice showed higher myelin coverage in the molecular layer compared to WT mice (Figure 7D, E)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“we found significantly more preserved myelin structure in the molecular layer of DG in P301S/LDLR and P301S/EKO mice compared to P301S mice by myelin basic protein (MBP) staining (Figure 7D, E).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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 our study, LDLR OX drastically reduces extracellular murine apoE that is mainly derived from astrocytes.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“LDLR OX upregulates Kv3.1 (Kcnc1) and Kv3.3 (Kcnc3).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
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
“OPCs in the corpus callosum trended at a higher density in apoE-deficient and LDLR-overexpressing mice with or without tau transgene (Figure 7I, K)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“One key finding of our study is the role of apoE in regulating microglial metabolism.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
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
“representing a population of activated microglia in neurodegeneration.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
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.
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
“This could suggest that LDLR OX and associated Apoe downregulation in microglia suppressed microglial activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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
“ApoE deficiency-associated activation of cell catabolism and suppression of cell anabolism likely constitute a crucial mechanism preventing microglial activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
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.
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
“indicating reduced mTOR activation and mTOR-mediated anabolism in apoE-deficient microglia in the setting of tauopathy.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
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.
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
“representing a population of reactive astrocytes.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
plain- 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.
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
“which may be related to apoE reduction.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
hedgedconditional- 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.
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 results suggest that Apoe downregulation was inherently associated with LDLR OX in microglia.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“indicating its potentially shared mechanisms with apoE-deficient microglia in elevating cell catabolism that was likely due to apoE reduction.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
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.
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
“suggesting that LDLR OX shares certain common mechanisms with apoE deficiency in controlling microglial metabolism, likely via apoE reduction.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
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.
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
“further supporting a key role of microglial Apoe in mediating LDLR’s protective effect.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
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.
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
“The distinctive upregulation of apoE in microglia in P301S mice highlights the potential role of microglia-derived apoE in neurodegeneration.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
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.
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
“thus representing homeostatic states.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
plain- 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.
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 results indicate that apoE-deficiency inherently suppresses mTOR activation upon microglial activation, likely by enhancing microglial catabolism.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
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.
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
“suggesting a potential role of proliferating OPCs in repairing damaged myelin in neurodegeneration.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
In the paper
“The uniquely high expression of Cspg4 and Pdgfra (Figure 7A) - markers of oligodendrocyte progenitor cells (OPCs, also known as NG2 glia) (Nishiyama et al., 2009), indicated that this cluster represented OPCs.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
What the sources say
- Not checked — no full text of the sourcecites Nishiyama et al., 2009 source
hedged- 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.
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
“The enlarged OPC pools in EKO and LDLR Tg mice may be essential in promoting oligodendrocyte genesis and maintaining myelin integrity under neurodegenerative conditions.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“indicating that apoE deficiency resulted in enhanced lysosomal functions under physiological conditions.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
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.
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
“indicating a specific population of microglia associated with disease but whose property was regulated by LDLR OX.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
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.
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
“suggesting that overexpressing LDLR is an effective approach to reduce extracellular brain apoE level via increased uptake and degradation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
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.
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
“The unique alteration in gene expression of these ion channels and receptors likely constitutes an important aspect of LDLR’s function in regulating microglial activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR-associated microglia upregulate genes encoding specific subsets of ion channels and neurotransmitter receptors and downregulate microglial activation pathways
hedgedconditional- 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.
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
“Thus, the reduced tau pathology and neurodegeneration upon LDLR OX may mainly result from attenuated microglial activation due to apoE reduction.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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
“this subset of microglia also appeared to be a type of activated microglia in the setting of apoE deficiency, as it clustered together with cluster 2 DAM microglia when using a lower resolution for cell clustering.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
hedgedcorrelational- 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.
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
“suggesting a key role of microglia in mediating the effect of apoE and LDLR on neurodegeneration.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
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.
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
“the increased difference in apoE level is likely due to aging-induced microglial activation that is stronger in WT microglia (with a higher degree of Apoe upregulation) than in LDLR microglia.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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.
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
“supporting a key role of apoE in p-tau pathogenesis.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice leads to a marked reduction of apoE and p-tau levels that strongly correlate with each other
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.
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
“Hence, increased Kv3 channel expression in microglia may reduce proinflammatory microglial activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
hedgedconditional- 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.
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, the protective effect may be partially due to reduction in this pool of apoE.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
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.
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
“suggesting intrinsic regulation of myelination by apoE/LDLR, likely in part through regulating OPCs.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“which was likely due to formation of doublets between a portion of microglia and oligodendrocyte nuclei instead of being real biological effects.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
hedgedconditionaln = 6- 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.
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 oligodendrocyte genes did not drive apoE-deficiency or LDLR-associated effects in microglia”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
plain- 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.
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
“Regulation of the OPC pool and myelin homeostasis by apoE/LDLR may constitute a new mechanism underlying their effects on neurodegeneration.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“The similar metabolic changes in apoE-deficient and TREM2-deficient microglia suggests that the inability to turn on the anabolic machinery in apoE-deficient microglia is likely a key mechanism preventing their activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
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.
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
“suggesting that LDLR itself may not significantly impact pathological tau spreading.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
hedged- 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.
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
“the effect of LDLR on suppressing microglial activation via apoE regulation may overwhelm any potential direct effects of LDLR on tau spreading.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
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.
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
“supporting their potential roles in maintaining myelin integrity.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“likely to clear damaged myelin.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
hedgedconditional- 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.
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
“Lower extracellular apoE level may also contribute to suppressed microglial activation through reduced microglial signaling.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
hedgedconditional- 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.
- Probably not a substantial claim. 31
- It may state two separate claims as one. 37
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“In a normal brain, apoE is produced predominantly by astrocytes, and to a much less extent, by microglia (Boyles et al., 1985; Uchihara et al., 1995).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
What the sources say
- Disputedcites Boyles et al., 1985 sourceExperimental — accuracy not yet measured
The Abstract reports apoE in astrocytes of rat brain but says it was not present in microglia. The Discussion likewise says most cells identified as microglia were negative for apoE immunoreactivity. The source therefore supports astrocytic production, but not the claim that normal-brain microglia produce apoE to a lesser extent. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites Uchihara et al., 1995 source
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.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“Astrocytes are another major immune-competent cell population in the brain, and have long been proposed to play a role in neurodegeneration (Ben Haim et al., 2015; Liddelow et al., 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
What the sources say
- Supportedcites Ben Haim et al., 2015 source
The Introduction states that reactive astrocytes and microglia mediate innate immune responses in the brain and that astrocytes become reactive during progressive neurodegenerative diseases. The disease-models section discusses astrocyte cytokine production in Alzheimer’s disease and inflammatory changes in ALS, supporting their proposed role in neurodegeneration. (LLM, conf=0.91)
- Supportedcites Liddelow et al., 2017 source
The Introduction describes astrocytes as abundant CNS cells that phagocytose synapses and respond to brain injury and disease. The section on human disease reports A1-like astrocytes in major neurodegenerative diseases, while the Concluding Remarks discuss their complement production and possible role in CNS immune responses. Together, these support the broad description of astrocytes as immune-competent cells implicated in neurodegeneration. (LLM, conf=0.88)
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
“Microglia express major classes of neurotransmitter receptors and ion channels that critically regulate microglial physiology, which inherently controls microglial function and activation (Domercq et al., 2013; Izquierdo et al., 2019).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR-associated microglia upregulate genes encoding specific subsets of ion channels and neurotransmitter receptors and downregulate microglial activation pathways
What the sources say
- Not matchedcites Domercq et al., 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Izquierdo et al., 2019 source
The Abstract states that essential microglial functions depend on ion channels, and the section on complex functions says ion channels and cell-surface receptors regulate microglial surveillance. The section on ramification and surveillance also describes adenosine, purinergic and adrenergic receptors in relation to microglial activation and process behavior. Together, these passages support the broad paraphrase. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ApoE strongly regulates brain amyloid-β (Aβ) deposition in a dose- and isoform-dependent manner (E4>E3>E2) (Bales et al., 1997; Holtzman et al., 2000; Schmechel et al., 1993).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Not checked — no full text of the sourcecites Bales et al., 1997 source
- Partly supportedcites Holtzman et al., 2000 sourceExperimental — accuracy not yet measured
The Results section reports greater Aβ deposition in apoE4- than apoE3-expressing mice, supporting the E4>E3 comparison. The paper does not test apoE2 or establish the claimed dose-dependent relationship; its Discussion proposes a concentration threshold rather than demonstrating a dose-response. Page numbers were not available in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Schmechel et al., 1993 source
boosteddirect- 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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Microglial depletion in P301S mice fully blocked neurodegeneration and stopped tau pathology progression.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Supportedcites Shi et al., 2019 source
The Results section reports that microglial depletion in TE4 mice, a P301S tauopathy model, virtually fully blocked neurodegeneration. The Discussion states that depletion fully blocked brain atrophy and halted progression of phosphorylated tau pathology. (LLM, conf=0.91)
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In the paper
“In an LDLR transgenic (Tg) mouse line, a PrP-driven Ldlr transgene was shown to be overexpressed in neurons and astrocytes by 10-fold, resulting in ~90% reduction of brain soluble apoE (Kim et al., 2009)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Supportedcites Kim et al., 2009 source
The Results (Generation and Characterization of LDLR Transgenic Mice; page not provided) describe a mouse-prion-promoter LDLR transgene, greater than tenfold overexpression in line B, and elevated LDLR in both neurons and astrocytes. The Results (LDLR Overexpression Decreases ApoE Levels; page not provided) report approximately 90% lower soluble apoE in cortical and hippocampal tissue from line B mice. (LLM, conf=0.91)
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In the paper
“LDLR Tg mice were generated in house previously on a B6/CBA background expressing murine LDLR under the PrP promoter (Kim et al., 2009).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > EXPERIMENTAL MODEL AND SUBJECT DETAILS
What the sources say
- Supportedcites Kim et al., 2009 source
The Experimental Procedures section, “Generation of LDLR Transgenic Mice” (page not provided), states that murine LDLR cDNA was inserted into a mouse prion promoter vector and that Washington University’s Mouse Genetics Core produced the transgenic mice on a B6/CBA background. The Results section confirms that the founders were maintained on that background. (LLM, conf=0.94)
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In the paper
“and is largely mediated by voltage-gated K+ channels, particularly Kv1.3, which critically regulates proinflammatory cytokine generation (Di Lucente et al., 2018).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Di Lucente et al., 2018 source
In the Results (page unavailable), LPS-stimulated mouse microglia showed outward voltage-gated K+ currents carried predominantly by Kv1.3, with some residual current in a small subset of cells. The Results also report that Kv1.3 knockout substantially reduced LPS-induced IL-1β and TNF-α levels and suppressed pro-inflammatory gene expression in microglia. The evidence supports the claim in the paper’s microglial, LPS-stimulated setting. (LLM, conf=0.90)
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In the paper
“ApoE’s effect appears to occur mainly in a cell-autonomous manner by regulating cellular cholesterol content, which critically regulates the level of membrane-associated signaling complexes that are essential for triggering cell proliferation (Murphy et al., 2011).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Murphy et al., 2011 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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In the paper
“The defective anabolic and energetic metabolism in TREM2-deficient microglia was shown to underlie their ineffective activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Ulland et al., 2017 source
The Results section reports impaired anabolic and energetic metabolism in TREM2-deficient microglia. The Discussion states that defective mTOR signaling severely impairs their capacity to respond to Aβ accumulation, supporting the claimed link between metabolic dysfunction and ineffective activation; page numbers were not available in our copy. (LLM, conf=0.91)
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In the paper
“TREM2-deficient microglia were reported to have increased autophagy and catabolism, impaired mTOR activation and anabolism, and reduced ATP production (Ulland et al., 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Partly supportedcites Ulland et al., 2017 sourceExperimental — accuracy not yet measured
The Results section on microglia reports increased autophagy, impaired mTOR signaling, and disrupted anabolic and energetic metabolism in TREM2-deficient microglia. The direct findings of increased catabolic products and depleted ATP are reported in bone marrow-derived macrophages, not microglia; ATP levels also do not directly establish reduced ATP production. The copy provides no page numbers for these passages. (LLM, conf=0.88)
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In the paper
“Microglia express a broad spectrum of neurotransmitter receptors and ion channels that critically regulate microglial functions such as surveillance (Madry et al., 2018), cytokine release (Nguyen et al., 2017), chemotaxis, and phagocytosis (Haynes et al., 2006; Koizumi et al., 2007; Ohsawa et al., 2007).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Madry et al., 2018 source
Madry et al. is cited for surveillance, not for the separately cited functions in the sentence. In Results, the paper reports that blocking THIK-1 inhibited microglial surveillance and that THIK-1 knockout reduced surveillance in brain slices and in vivo. (LLM, conf=0.94)
- Supportedcites Nguyen et al., 2017 source
The Nguyen et al. citation is attached specifically to cytokine release, not to surveillance, chemotaxis, or phagocytosis. The Abstract reports that blocking Kv1.3 or KCa3.1 inhibited pro-inflammatory cytokine production in microglia, and the Discussion identifies IL-1β and TNF-α among the affected cytokines. (LLM, conf=0.93)
- Partly supportedcites Haynes et al., 2006 sourceExperimental — accuracy not yet measured
The chemotaxis experiments (p. 43) show that P2Y12-deficient microglia lack directed movement toward ADP or ATP, supporting the receptor-regulated chemotaxis portion of the citation. The Introduction (Chapter 1) says activated microglia can phagocytose debris, but the cited paper does not show that receptors or ion channels regulate phagocytosis. The paper discusses several purinergic receptors rather than establishing the full breadth of neurotransmitter receptors and ion channels in the citing sentence. (LLM, conf=0.87)
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In the paper
“The ability of apoE to inhibit cell proliferation has also been reported in other cell types, such as hippocampal neural stem/progenitor cells (NSC/NPC) (Yang et al., 2011) and hematopoietic cells (Murphy et al., 2011).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Yang et al., 2011 source
The rescue experiment reports that re-expressing ApoE reduced BrdU incorporation in neural progenitor cells. The Discussion also states that ApoE inhibits neural stem/progenitor-cell proliferation in the dentate gyrus. Yang et al. is cited for the hippocampal-cell part of the sentence, not the hematopoietic-cell part; page numbers are not provided in our copy. (LLM, conf=0.94)
- Supportedcites Murphy et al., 2011 source
The Murphy et al. citation is attached to hematopoietic cells, not hippocampal neural stem/progenitor cells. The Discussion reports that ApoE suppresses proliferation of hematopoietic stem and progenitor cells (HSPCs); the supplied passage does not specify a page. (LLM, conf=0.94)
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In the paper
“The other primary apoE metabolic receptor, LRP1, has been shown to mediate tau uptake in vitro and drastically increase the propagation of the P301L human tau protein expressed by an AAV virus in vivo (Rauch et al., 2020)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Rauch et al., 2020 source
The Results report that LRP1 knockdown reduced tau uptake in cultured cells and greatly diminished tau spread in mice compared with controls. The Methods (Animals; page not specified) identify the in vivo construct as AAV-encoded human tau P301L. (LLM, conf=0.92)
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In the paper
“APOE and TREM2 act in the same axis in regulating many aspects of microglial functions (Shi and Holtzman, 2018).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Shi and Holtzman, 2018 source
The review describes an ApoE–TREM2 axis in microglial phagocytosis (Immune functions of ApoE in neurodegeneration) and shared pathways regulating the microglial neurodegenerative phenotype (same section). It also links both proteins to microglial responses to amyloid-β plaques (ApoE and amyloid-β pathology), supporting the claim across multiple functions. (LLM, conf=0.88)
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In the paper
“A recent study shows that selective removal of astrocyte-derived apoE4 (but not apoE3) reduces tau-associated neurodegeneration (Wang et al., 2021).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Wang et al., 2021 source
The Discussion (page unavailable) states that genetic deletion of astrocytic APOE4, but not APOE3, was significantly neuroprotective in P301S Tau mice. This directly supports the cited comparison in a mouse model of tauopathy. (LLM, conf=0.95)
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In the paper
“Interestingly, TREM2 deficiency also protects against tau-associated neurodegeneration in P301S mice (Leyns et al., 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Supportedcites Leyns et al., 2017 source
The Results section identifies PS19 mice as expressing P301S-mutant human tau and reports less brain atrophy and synaptic degeneration in TREM2-deficient PS19 mice than in controls. The authors conclude that loss of TREM2 function is neuroprotective in this tauopathy model; the study examined male mice only. (LLM, conf=0.94)
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In the paper
“whereas minimal levels of these gene expression changes and no differences in their expression level were observed in microglia isolated from 3-month mice (Figure 3K).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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In the paper
“cluster 2 was specifically enriched in P301S mice (Figure 5A, B), and featured hallmark “DAM/MGnD” genes such as Apoe, Spp1, Cd74, Lilrb4a, Itgax, Axl, Trem2 and B2m (Figure 5C, E)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
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In the paper
“LDLR OX in P301S mice attenuated tau pathology, shifting p-tau staining towards an early-disease pattern (type1) (Figure 1H).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX in P301S mice attenuates neurodegeneration, synaptic loss and tau pathology
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In the paper
“Compared to cluster 2 “DAM” microglia, a prominent feature of cluster 4 microglia was upregulation of catabolic genes, and downregulation of anabolic genes as well as microglial activation pathways (Figure 5F).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
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In the paper
“neurodegeneration in P301S mice featured loss of specific subtypes of excitatory hippocampal neurons, including dentate gyrus (DG), CA1 and CA3 neurons, particularly DG neurons, but had little impact on subiculum neurons (Figure 4C, D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
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In the paper
“in P301S mice, apoE immunostaining revealed intracellular apoE accumulation as large bright puncta in activated microglia; whereas in WT mice, apoE signal was primarily present in astrocytes (Figure S4B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
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In the paper
“We obtained sequencing data from a total of 31785 nuclei, and identified 10 distinct cell clusters across all samples based on the expression of known cell-type-specific markers”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
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In the paper
“We performed sub-clustering of astrocytes (pooled from all samples, a total of 1863 nuclei), and identified homeostatic astrocyte populations and a reactive astrocyte subset, as well as a subpopulation of astrocytes enriched in apoE-deficient mice (EKO and P301S/EKO) (Figure 6A, B).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
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In the paper
“Notably, cluster 3 was uniquely enriched in P301S/LDLR mice (Figure 5A, B), but not in LDLR mice”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglia sub-clustering reveals distinct microglial subpopulations associated with neurodegeneration, apoE deficiency, or LDLR-OX
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Compared to P301S mice, Apoe expression in P301S/LDLR mice was notably lower in microglia, but was only mildly reduced in astrocytes (Figure S4A)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
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In the paper
“We verified by immunofluorescent staining (GFAP, Vimentin) that reactive astrocytes were highly activated in 9-month P301S mice, but were only mildly increased in P301S/LDLR and P301S/EKO mice (Figure 6F).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Astrocyte sub-clustering identifies features of homeostatic and reactive astrocytes
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In the paper
“Biochemically, no differences in tau or ptau levels were detected despite a similar level of apoE reduction in P301S/LDLR mice (Figure S2C).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR OX does not affect tau pathology and brain volume at an early age prior to microglial activation
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In the paper
“we found microglial Apoe expression was significantly elevated in 20-month WT mice, but not in 20-month LDLR Tg mice compared to their 3-month counterparts (Figure 3J).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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In the paper
“We confirmed higher expression of top upregulated genes such as Gabra6 and Grm4 in acutely isolated microglia from 20-month LDLR Tg mice compared to WT mice, whereas no differences were observed in 3-month mice (Figure S5C, D).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR-associated microglia upregulate genes encoding specific subsets of ion channels and neurotransmitter receptors and downregulate microglial activation pathways
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In the paper
“Notably, microglia were markedly increased in P301S mice, and were only mildly increased in P301S/LDLR and P301S/EKO mice”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Single-nuclei RNAseq identifies changes in distinct brain cell populations and in cell-type-specific DEGs under neurodegenerative, apoE-deficient and LDLR-OX conditions
plaincorrelationaln = 8- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduction of microglial Apoe expression (Figure 3G) and intracellular apoE protein levels was also observed in acutely-isolated LDLR Tg microglia (Figure 3H, I).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Microglial overexpression of the LDLR transgene reduces microglial Apoe expression and intracellular apoE level and is associated with less microglial activation
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In the paper
“In contrast, upregulated pathways featured “regulation of synaptic plasticity”, “regulation of ion transport”, and “regulation of membrane potential”.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > LDLR-associated microglia upregulate genes encoding specific subsets of ion channels and neurotransmitter receptors and downregulate microglial activation pathways
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In the paper
“Through electron microscopy, we also identified notable signs of myelin damage in the corpus callosum of 9-month P301S mice, which showed a significantly higher percentage of demyelinated axons as well as increased axonal G-ratio compared to 9-month P301S/LDLR and P301S/EKO mice, or 3-month P301S mice (Figure 7F, G).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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“these effects were either not present or only weakly showed up in oligodendrocytes.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
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“A portion of microglia from all 6 groups of mice show expression of certain oligodendrocyte genes”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
plainn = 6- 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 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
“whereas apoE deficiency-associated microglia showed enhanced catabolism and suppressed anabolism.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
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 paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“LDLR Tg microglia showed a similar metabolic pattern and reduced activation as apoE-deficient microglia, likely in part due to cell-autonomous reduction in Apoe expression.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
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 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
“Axonal demyelination and altered G-ratio also occurred in the corpus callosum of 24-month old WT mice relative to 9-month WT mice, and this damage was significantly attenuated in 24-month LDLR Tg and EKO mice (Figure S6A-C).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells in the brain and show greater preservation of myelin integrity under neurodegenerative conditions
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.
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
“we find LDLR OX leads to a strong reduction in extracellular apoE levels and microglial Apoe downregulation that are directly linked with suppressed microglial activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Activated immune cells increase anabolism and rewire their metabolism towards enhanced glycolysis (Bories and Leitinger, 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency-associated microglia downregulate anabolic pathways and show robust upregulation of catabolic genes
What the sources say
- Not checked — no full text of the sourcecites Bories and Leitinger, 2017 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“APOE4 strongly increases the risk of developing late-onset Alzheimer’s disease (AD), whereas APOE2 reduces AD risk relative to APOE3 (Bu, 2009).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Introduction
What the sources say
- Not matchedcites Bu, 2009
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- 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.
- Not matched
In the paper
“ApoE expression in neurons is minimal under physiological conditions, but can be upregulated upon neuronal injury in certain conditions (Xu et al., 2006).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > Apoe expression is upregulated uniquely in microglia over other brain cell types in tau-associated neurodegeneration
What the sources say
- Not matchedcites Xu et al., 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainconditional- 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.
- Not matched
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
“A total of 31,785 individual nuclei across all genotypes remained, with a median of 1,620 UMIs and 871 genes per nucleus for downstream analysis.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
plainn = 31,785- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In addition, the high expression of GABA receptor (Gabra6, second most enriched DEG in cluster3 microglia) may also play a role in inhibiting microglial cytokine release (Kuhn et al., 2004) and attenuating microglial activation.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Not checked — no full text of the sourcecites Kuhn et al., 2004 source
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. It may state two separate claims as one.
In the paper
“Proinflammatory “M1” microglia show a profound metabolic change characterized by increased glucose uptake and a switch from oxidative phosphorylation (OXPHOS) to glycolysis even in normoxic conditions (Warburg effect) (Bories and Leitinger, 2017).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Not checked — no full text of the sourcecites Bories and Leitinger, 2017 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Microglia derived from individual P2 pups (mixed sex) were cultured separately as independent samples.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > EXPERIMENTAL MODEL AND SUBJECT 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
“Oligodendrocyte genes and pathways showing up in microglial analysis results were excluded.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
plainn = 6- 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
“LDLR OX also increases the OPC population, which is likely due to apoE reduction, or may also be contributed by a direct effect of LDLR on cellular lipid/cholesterol homeostasis.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
hedgedconditional- 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.
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
“ApoE reduction doesn’t affect early tau pathology prior to microglial activation, suggesting that its protective effect on tau pathology is likely carried out at a later stage by regulating microglial activation under neurodegenerative conditions.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
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.
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 quality control, nuclei with mitochondrial content >5% were removed.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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
“filter reads with a quality score below 30.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Modulating LRP1 has also been reported to affect brain apoE levels (Liu et al., 2007; Zerbinatti et al., 2006)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The adjusted P-value was calculated using Bonferroni correction.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Development of outward K+ current in microglia is associated with an advanced microglial activation status (Boucsein et al., 2000; Wendt et al., 2017)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For all experiments, data normality was analyzed using D’Agostino-Pearson omnibus normality test.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
In the paper
“The Kv3 channels have a 10-50 mV higher activation threshold than any other known mammalian voltage-gated K+ channels (Coetzee et al., 1999).”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Discussion
What the sources say
- Not checked — no full text of the sourcecites Coetzee et al., 1999 source
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
“ptau ELISA detects ptau species that have phosphorylation at both Thr181 and Ser202/Thr205 epitopes, which represent hyperphosphorylated ptau.”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > 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.
The paper relies on this without support.
Male P301S mice start developing overt tau pathology from ~5-6 months of age and show severe brain atrophy at 9 months of age.
“Male P301S mice start developing overt tau pathology from ~5-6 months of age and show severe brain atrophy at 9 months of age.”
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
“As these molecules play critical roles in Aβ clearance and tau aggregation,41,42 the ε7 isoform may influence AD pathology through these pathways.”
From Association of rare APOE missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [42]
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
“Therefore, apoE4 accelerates AD pathogenesis by inducing dysregulation of microglia and astrocytes and provoking neuroinflammation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Shi et al 2021
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
“overexpression of LDLR is an effective approach to significantly induce apoE reduction and consequent alleviation of pathological changes in AD mouse models”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Shi et al 2021
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It is notable that overexpression of Ldlr also reduced tau pathology and neurodegeneration in a tauopathy mouse model,”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [74]
The cited source says what the claim attributes to it.
In the citing paper
“previous studies have demonstrated that deletion of Apoe and overexpression of Ldlr can reduce tau‐associated neurodegeneration.”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [74]
The cited source says what the claim attributes to it.
In the citing paper
“Overexpression of LDLR reduced ApoE levels and reduced tau-mediated neurodegeneration (63).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [63]
The cited source says what the claim attributes to it.
In the citing paper
“important roles were shown for LDLR in modulating AD pathologies57–59, in part via uptake and clearance of Aβ by astrocytes60.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [59]
The cited source says what the claim attributes to it.
In the citing paper
“Shi et al. [86] report that overexpression of LDLR in PS19 mice suppresses microglial activation, enlarges pools of oligodendrocyte progenitor cells, and enhances preservation of myelin integrity.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“Apoe knockout mice and LDL receptor (Ldlr)-overexpressing mice — which display low levels of APOE owing to internalization and clearance of APOE lipoproteins — have larger pools of oligodendrocyte progenitor cells and increased myelin coverage of axons, supporting the idea that APOE regulates oligodendrocyte number and function106.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [106]
The cited source says what the claim attributes to it.
In the citing paper
“overexpression of LDLR in PS19 tauopathy mice also results in a significant reduction of brain apoE levels and inhibition of tau phosphorylation, which strongly correlate with one another, and consequent amelioration of tau pathology and neurodegeneration”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Shi et al 2021
The cited source says what the claim attributes to it.
In the citing paper
“Overexpression of the ApoE receptor LDLR in the brain decreases tau mediated neurodegeneration [90].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [90]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > Results > ApoE deficiency boosts microglial lysosomal enzyme activities under physiological conditions, and reduces microglial mTOR activation and lipid/cholesterol accumulation upon microglial activation
“N-Acetyl-Alpha-Glucosaminidase (Naglu)”
§ Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms > STAR★Methods > METHOD DETAILS
“4-Methylumbelliferyl N-acetyl-β-D-glucosaminide (Naglu Substrate)”
Citations
Cites
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
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Zeisel, A., Muñoz-Manchado, A. B., Codeluppi, S., Lönnerberg, P., La Manno, G., Juréus, A., Marques, S., Munguba, H., He, L., Betsholtz, C., et al. (2015) · Science · doi:10.1126/science.aaa1934 · Cited by 3,124
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Self-citationSingle-cell transcriptomic analysis of Alzheimer’s disease
Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J. Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al. (2019) · Nature · doi:10.1038/s41586-019-1195-2 · Cited by 2,568
The P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542
Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9649 · Cited by 1,525
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263
Self-citationApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220
Self-citationApolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168
Cited by
Sorted by citations
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278
APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
Parhizkar, S., & Holtzman, D. M. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101594 · Cited by 255
Self-citationCell type‐specific roles of APOE4 in Alzheimer disease
Blumenfeld, J., Yip, O., Kim, M. J., & Huang, Y. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00776-9 · Cited by 202
Lipid-accumulated reactive astrocytes promote disease progression in epilepsy
Chen, Z.-P., Wang, S., Zhao, X., Fang, W., Wang, Z., Ye, H., Wang, M.-J., Ke, L., Huang, T., Lv, P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01288-6 · Cited by 214
Metadata
- Authors
- Shi, Y., Andhey, P. S., Ising, C., Wang, K., Snipes, L. L., Boyer, K., Lawson, S., Yamada, K., Qin, W., Manis, M., Serrano, J. R., Benitez, B. A., Schmidt, R. E., Artyomov, M., Ulrich, J. D., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University Hospital Bonn (DE)
- The University of Tokyo (JP)
- Corresponding author
- Ulrich, Jason D.
- Holtzman, David M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 109
- Issue
- 15
- Pages
- 2413-2426.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8349883
- OpenAlex
- W3177458716
- Semantic Scholar
- 1544f9b83b6ce89b91dbee8712a9dde8dab78e8d
- Cited by
- 135
- References
- 55
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 25 · 2023: 21 · 2022: 28 · 2021: 9
- FWCI
- 13.02
- 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, 368 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
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DZNE Pub (submittedVersion)
- Funders
- JPB Foundation
- National Institutes of Health (AG047644, NS090934)
- University of Washington
- Genentech
- Diabetes Research Center
- Tau Consortium
- Merck
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- LDL receptor, apolipoprotein E, tauopathy, Alzheimer's disease, microglial activation, oligodendrocyte precursor cells, myelin integrity, reactive astrocytes, ion channels, neurotransmitter receptors, neurodegeneration
- MeSH terms
- Animals, Apolipoproteins E, Male, Nerve Degeneration, Receptors, LDL, Microglia, Mice, Knockout, Tauopathies, Mice
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 2026-11-02, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-02 (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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