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Cited by 93Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyMitochondrial Function and Pathology

ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

Open access
Lee, Hyein, Cho, Sukhee, Kim, Mi-Jin, Park, Yeo Jin, Cho, Eunji, Jo, Yeon Suk, Kim, Yong-Seok, Lee, Jung Yi +10 more·2023·Cell Reports
DOI 10.1016/j.celrep.2023.113183
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Abstract

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

AI snapshot

Written from the paper’s full text.

TL;DR

Using isogenic human iPSC-derived astrocytes, this study shows that ApoE4 increases glycolysis but impairs mitochondrial respiration and oxidative phosphorylation. ApoE4-dependent lysosomal cholesterol accumulation disrupts autophagy/mitophagy, and cholesterol depletion restores mitochondrial homeostasis and respiration but not glycolytic activity.

Key findings

  • ApoE4 astrocytes showed increased glycolytic activity, including higher ECAR, increased lactate release, and increased m+3 lactate from 13C-glucose tracing, compared with isogenic ApoE3 astrocytes.
  • ApoE4 astrocytes had reduced mitochondrial respiration: lower basal respiration, maximal respiration, ATP-linked respiration, and reserve capacity, with increased mitochondrial ROS by MitoSOX.
  • ApoE4 astrocytes accumulated cholesterol predominantly in lysosomes, had enlarged lysosomes, increased LysoTracker area/intensity, and approximately 50% higher cathepsin B activity; they also showed impaired autophagy flux with increased p62/LC3 and increased autophagosomes but decreased autolysosomes.
  • MβCD treatment (100 μM, 4 days) reduced lysosomal cholesterol and restored autophagy flux and mitochondrial ultrastructure; 14 days of MβCD restored mitochondrial respiration but did not normalize glycolytic activity. Proteomics found 254 downregulated and 238 upregulated proteins in ApoE4 astrocytes, with 16 downregulated and 34 upregulated proteins restored by MβCD.

Methods

  • Isogenic ApoE3/ApoE4 human iPSC-derived astrocytes were generated from an AD patient-derived APOE4 line edited to APOE3 by CRISPR-Cas9, another healthy-individual-derived isogenic pair, and the KOLF2.1J reference line with isogenic ApoE4; astrocytes were differentiated, FACS-sorted by GLAST, and validated by astrocyte markers.
  • Metabolic and mitochondrial assays included Seahorse ECAR/OCR, Lactate-Glo, 13C-glucose metabolic flux analysis, MitoSOX staining, RNA-seq/GSEA, FRET-based Laconic lactate sensing, LysoTracker/MitoTracker imaging, filipin III cholesterol staining, RFP-GFP-LC3 autophagy flux, cathepsin B activity, electron microscopy, and proteomics.
  • Cholesterol-lowering treatments used methyl-β-cyclodextrin (MβCD) and simvastatin; statistical analysis used unpaired Student’s t-test or one-way ANOVA with Dunnett’s post hoc analysis.

Limitations

  • The paper states that astrocytes were cultured with serum for expansion and serum-deprived for 4 days before experiments, but early serum exposure may still alter transcriptome, morphology, and function compared with cells never exposed to serum.
  • The paper states that cholesterol mitigation rescued autophagy and mitochondrial abnormalities, but enhanced glycolytic activity was not fully restored even after long-term lysosomal cholesterol depletion; whether increased glycolysis precedes cholesterol accumulation or is cholesterol independent remains to be addressed.
  • The paper notes that other adverse effects of disrupted lysosomal function by cholesterol could indirectly cause mitochondrial dysfunction, and that increased circular mitochondria on electron microscopy did not directly prove altered mitochondrial biogenesis/turnover or its causal relationship with metabolic abnormality; an evident limitation is the in vitro hiPSC-derived astrocyte system without in vivo validation.

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

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2023.113183

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

37 of 48 cited sources checked · 8 supported · 2 flagged · accuracy not yet measured

  • Premisecitation
    § Discussion

    None of the previous studies attempted to provide causality among these pathological features and to restore the defects by ApoE4, especially in human astrocytes.

    “However, none of these studies attempted to provide the causality among these pathological features and to restore the defects by ApoE4, especially in human astrocytes.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [4] Farmer, 2021, APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis, Mol. Neurodegener. source

      The Materials and methods (Cell culture; page unavailable) describe mouse-derived astrocytes expressing human APOE alleles, not human astrocytes. The Results (Stable isotope resolved metabolomics; page unavailable) compare metabolic changes in E3 and E4 mice and astrocytes; the passages do not describe restoring those defects. This supports the characterization of this paper, but it cannot establish the broader claim about what none of the other studies attempted, or which pathological features they investigated for causality. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [9] Qi, 2021, ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism, Cell Rep. source

      The Introduction identifies unanswered questions about ApoE variants and fatty-acid metabolism, but it does not say that none of the previous studies investigated causality or attempted to restore ApoE4-related defects. The Methods (page unavailable) describe astrocytes isolated from mice with humanized ApoE, not human astrocytes. Searches for causal relationships, restoration, and human astrocytes found no passage establishing the claim about previous studies. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [23] Wu, 2018, Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer’s Disease Risk Reduction and Early Intervention, J. Neurosci. source

      The Results section reports an intervention aimed at reversing ApoE4-associated deficits: PGC-1α overexpression in ApoE4-expressing N2a cells improved hexokinase activity and reversed defects in glycolytic reserve capacity. This contradicts the claim that none of the studies attempted to restore ApoE4-related defects. The experiment used N2a cells, not human astrocytes; our copy does not establish the broader claim about all previous studies. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation
    § Results

    ApoE4 astrocytes display impaired Aβ clearance compared with ApoE3 astrocytes.

    “ApoE4 astrocytes displayed reduced levels of ApoE and impaired Aβ clearance compared with ApoE3 astrocytes”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Lin, 2018, APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types, Neuron source
  • Findingcitation
    § Results

    ApoE4 astrocytes display reduced levels of ApoE compared with ApoE3 astrocytes.

    “ApoE4 astrocytes displayed reduced levels of ApoE and impaired Aβ clearance compared with ApoE3 astrocytes”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Lin, 2018, APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types, Neuron source
  • Study design and conductcitation
    § Discussion

    Three ApoE3 and ApoE4 isogenic iPSC pairs were used to determine the effect of APOE4 genotype without inter-donor variability.

    “Three ApoE3 and ApoE4 isogenic iPSCs pairs were used to determine the effect of APOE4 genotype without inter-donor variability.5”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Lin, 2018, APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types, Neuron source

      The Results sections on generating APOE4 iPSCs and converting APOE4 to APOE3 describe isogenic comparisons, which allow APOE genotype to be examined within a donor background. They describe one pair derived from an unaffected subject and another from a sporadic AD patient, not three pairs. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [12] Pantazis, 2022, A reference human induced pluripotent stem cell line for large-scale collaborative studies, Cell Stem Cell source

      The Introduction says that genetic background can influence iPSC phenotypes and describes the value of isogenic comparisons. The Results identify APOE E4 in two cell lines, but neither passage reports using three APOE3/APOE4 isogenic pairs to assess genotype effects. Searches for the pairs and inter-donor variability found no passage establishing that study design. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [40] Meyer, 2019, REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease, Cell Rep. source

      The Results section (‘APOE4 Induces Early Neuronal Differentiation and Dysregulation of REST’; page not provided) says the authors used isogenic iPSC lines differing only in APOE genotype to study its effects, which supports the rationale of avoiding inter-donor differences within a comparison. It describes editing lines from two donor backgrounds, not using three isogenic APOE3/APOE4 pairs. The three biological replicates reported in Methods are organoid samples, not three pairs. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Interpretationreasoning
    § Discussion

    Detrimental effects of impaired mitochondrial respiration in ApoE4 astrocytes could be magnified in later stages of life when the brain's metabolic dependency transitions from aerobic glycolysis to mitochondrial respiration.

    “Thus, the detrimental effects of impaired mitochondrial respiration in ApoE4 astrocytes could be magnified in the later stages of life when the transition of metabolic dependency of the brain from aerobic glycolysis to mitochondrial respiration occurs.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Goyal, 2017, Loss of Brain Aerobic Glycolysis in Normal Human Aging, Cell Metab. source

      The Results and Discussion section (‘Whole brain AG decreases with age’; page unavailable) reports that aerobic glycolysis declines with age while whole-brain oxygen use remains relatively unchanged, supporting a shift in the relative contribution of these metabolic pathways. The paper studies cognitively normal human brains, not ApoE4 astrocytes, and does not test whether impaired mitochondrial respiration becomes more harmful later in life. It also does not establish a discrete transition to dependence on mitochondrial respiration. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 20

  • Classified as probably not a substantial claim.

    Premisecitation
    § Results

    Cholesterol accumulation in lysosomes impairs lysosomal functions, including autophagy-mediated mitochondrial degradation, in various pathological conditions, including Niemann-Pick disease type C.

    “Cholesterol accumulation in lysosomes has been shown to impair lysosomal functions, including autophagy-mediated mitochondrial degradation, in various pathological conditions, including Niemann-Pick disease type C.15”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Maetzel, 2014, Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells, Stem Cell Rep. source

      The Results section on the NPC1 mutation reports both cholesterol accumulation and impaired autophagic flux, but says that depleting cholesterol did not rescue the autophagy defect. It instead links the defect to loss of NPC1 function, contrary to the claimed causal role of cholesterol accumulation in NPC. The paper does not specifically report impaired autophagy-mediated mitochondrial degradation. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [16] Davis, 2021, NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C, Dev. Cell source

      The Introduction links lysosomal cholesterol accumulation in NPC1-deficient cells to lysosomal dysfunction, and the Results report impaired steps in mitophagy, the autophagic clearance of mitochondria (page numbers unavailable). The paper supports the claim for Niemann-Pick type C, but does not establish that cholesterol accumulation causes these effects across the various other pathological conditions claimed. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Introduction

    Abnormal glucose metabolism is one of the major pathological features of Alzheimer's disease and is observed in the early phase of disease progression.

    “Abnormal glucose metabolism is one of the major pathological features of Alzheimer’s disease (AD) and is observed in the early phase of disease progression.1”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] Gordon, 2018, Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer disease: a longitudinal study, Lancet Neurol. source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Introduction

    Recent studies on human induced pluripotent stem cells with the APOE4 variant showed altered transcriptomic and metabolomic profiles toward the accumulation of cholesterol in glia, such as astrocytes and oligodendrocytes.

    “Recent studies on human induced pluripotent stem cells (iPSCs) with the APOE4 variant showed altered transcriptomic and metabolomic profiles toward the accumulation of cholesterol in glia, such as astrocytes and oligodendrocytes.5”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Lin, 2018, APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types, Neuron source

      The Results section (“APOE4 astrocytes exhibit compromised Aβ uptake”; page unavailable) reports altered lipid-metabolism gene expression and increased cholesterol in APOE4 iPSC-derived astrocytes. It does not report cholesterol accumulation in oligodendrocytes or a metabolomic profile; cholesterol was measured with targeted assays. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [6] Victor, 2022, Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity, Cell Stem Cell source

      The Results section, “Imbalance in the net flux of lipids by APOE4 iMGLs” (page unavailable), reports transcriptional profiling and increased extracellular cholesterol in APOE4 iPSC-derived microglia. The Discussion section, “Cholesterol homeostasis” (page unavailable), reports prior findings of extracellular cholesterol accumulation in APOE4 iPSC-derived astrocytes. The cited paper does not report this finding for oligodendrocytes or describe the claimed metabolomic profiling. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [7] TCW, 2022, Cholesterol and matrisome pathways dysregulated in astrocytes and microglia, Cell source

      The Results sections on altered lipid metabolism and impaired cholesterol trafficking report APOE4-associated transcriptomic changes and increased intracellular cholesterol in hiPSC-derived astrocytes, supported by cholesterol measurements. The paper studies astrocytes and microglia, not oligodendrocytes, and the cited passages do not establish altered metabolomic profiles across glial cell types. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Introduction

    Altered brain metabolism, especially increased aerobic glycolysis and impaired oxygen consumption in the brains of ApoE4 carriers, is suggested by studies from human plasma and humanized mouse models.

    “Altered brain metabolism, especially increased aerobic glycolysis and impaired oxygen consumption in the brains of ApoE4 carriers, is suggested in studies from human plasma and humanized mouse models.2”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [2] Ercoli, 2006, Perceived Loss of Memory Ability and Cerebral Metabolic Decline in Persons With the Apolipoprotein E-IV Genetic Risk for Alzheimer Disease, Arch Gen Psychiat source
    • cites [3] Cho, 2021, Impact of Genetic Risk Factors for Alzheimer’s Disease on Brain Glucose Metabolism, Mol. Neurobiol. source
    • cites [4] Farmer, 2021, APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis, Mol. Neurodegener. source

      The Results and Discussion report increased aerobic glycolysis in brains of mice expressing human APOE4, alongside decreased oxygen consumption in E4 astrocytes. In human participants, the paper measured plasma metabolites and whole-body oxygen consumption, not oxygen consumption in carriers’ brains. The claim therefore extends the oxygen-consumption finding beyond the tissue measured. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    Inhibiting lactate transfer from astrocytes to neurons abolishes hippocampal and cortical synaptic plasticity under stress conditions in mice.

    “Another study reported that inhibiting lactate transfer from astrocytes to neurons abolished hippocampal and cortical synaptic plasticity under stress conditions in mice.38”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Murphy-Royal, 2020, Stress gates an astrocytic energy reservoir to impair synaptic plasticity, Nat. Commun. source

      In Results, “Astrocyte to neuron lactate shuttle is impaired by stress” (page unavailable), inhibiting lactate transport abolished lactate-mediated rescue of neocortical LTP in stressed mice. The hippocampal experiment instead found that stress reduced—but did not abolish—LTP and that supplying lactate rescued it; it did not show that inhibiting lactate transfer abolished hippocampal plasticity. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    The astrocyte-neuron lactate shuttle regulates neuronal activity.

    “Increased levels of lactate have also been shown to be correlated with neuronal network activity, as the astrocyte-neuron lactate shuttle is known to regulate neuronal activity.31”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Suzuki, 2011, Astrocyte-neuron lactate transport is required for long-term memory formation, Cell source

      The Results section reports that training increased hippocampal lactate and that blocking glycogen metabolism disrupted maintenance of hippocampal long-term potentiation, an effect rescued by lactate. This supports a role for astrocyte–neuron lactate transport in activity-related synaptic plasticity, but the paper does not directly establish a correlation between lactate levels and neuronal network activity or show regulation of baseline neuronal activity. Page numbers were unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    Pathological changes in AD brains precede the onset of clinical symptoms, and one of the first alterations, along with Aβ accumulation, is dysfunctional glucose metabolism.

    “Pathological changes in AD brains precede the onset of clinical symptoms, and one of the first alterations, along with Aβ accumulation, is dysfunctional glucose metabolism.1”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [1] Gordon, 2018, Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer disease: a longitudinal study, Lancet Neurol. source

      The Discussion reports that Aβ deposition was the first neuroimaging biomarker to differ between groups, followed by metabolic decline, both well before expected dementia onset. The study examined families with autosomal dominant AD; it does not establish that this timing applies to AD brains generally. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [27] Weise, 2018, Left lateralized cerebral glucose metabolism declines in amyloid-β positive persons with mild cognitive impairment, Neuroimage. Clin. source
    • cites [28] Croteau, 2018, A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease, Exp. Gerontol. source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Results

    The half-life of mitochondria is a couple of weeks in several cell types.

    “The half-life of mitochondria is known to be a couple of weeks in several cell types,20”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [20] Krishna, 2021, Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain, Dev. Cell source

      The Results section reports mitochondrial-protein half-lives in two cell types: 7 days in neurons and 5.5 days in myotubes. That supports the broader point that mitochondrial turnover varies by cell type, but it does not establish a roughly two-week half-life for mitochondria themselves; the paper says the lifespan of individual mitochondria is unknown. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [21] Facundo, 2017, Mitochondria and Cardiac Hypertrophy, Adv. Exp. Med. Biol. source
    • cites [22] Menzies, 1971, The Turnover of Mitochondria in a Variety of Tissues of Young Adult and Aged Rats, J. Biol. Chem. source

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

    Premisecitation
    § Discussion

    Increased levels of lactate are correlated with neuronal network activity.

    “Increased levels of lactate have also been shown to be correlated with neuronal network activity, as the astrocyte-neuron lactate shuttle is known to regulate neuronal activity.31”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Suzuki, 2011, Astrocyte-neuron lactate transport is required for long-term memory formation, Cell source

      The Results section, “Learning-induced astrocytic release of lactate is required for memory formation” (page unavailable), reports that hippocampal lactate increased after training. The Introduction and Discussion link lactate transport to neuronal activity, but the paper does not report a direct correlation between lactate levels and measured neuronal network activity. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    Young ApoE4 carriers showed increased brain activity in default network regions, as well as in the hippocampus and the temporal lobe, possibly due to increased aerobic glycolysis.

    “Young ApoE4 carriers showed increased brain activity in default network regions, as well as in the hippocampus and the temporal lobe, possibly due to increased aerobic glycolysis.34”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [34] Vlassenko, 2010, Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ ) deposition, Proc. Natl. Acad. Sci. USA source
    • cites [35] Filippini, 2009, Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele, Proc. Natl. Acad. Sci. USA source

      The Results report greater default-mode-network coactivation in medial temporal, medial-prefrontal, and retrosplenial regions, as well as greater hippocampal activation during memory encoding in young APOE ε4 carriers. They do not establish a separate increase across the temporal lobe or suggest increased aerobic glycolysis as an explanation; the Discussion considers other possible mechanisms. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    Increased cholesterol levels can be caused by enhanced glycolysis and the subsequent synthesis of acetyl-CoA, a source of cholesterol synthesis.

    “Increased cholesterol levels can be caused by enhanced glycolysis and the subsequent synthesis of acetyl-CoA, a source of cholesterol synthesis,39”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Shi, 2022, Intracellular Cholesterol Synthesis and Transport, Front. Cell Dev. Biol. source

      The Introduction’s “Cholesterol Synthesis” section identifies acetyl-CoA as a starting material for cholesterol synthesis. It does not say that enhanced glycolysis increases acetyl-CoA production or causes cholesterol levels to rise; searches for glycolysis and that proposed link found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    Lactate levels in the interstitial fluid were higher in patients than in unaffected individuals.

    “Lactate levels in the interstitial fluid were higher in patients than those in unaffected individuals.29”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Carroll, 2019, The Interaction Between Sleep and Metabolism in Alzheimer’s Disease: Cause or Consequence of Disease?, Front. Aging Neurosci. source

      The “Glucose Metabolism and Neuronal Activity in AD” section (page unavailable) reports increased interstitial-fluid lactate after induced hyperglycemia in rodents, with a greater effect in mice with substantial amyloid pathology. It does not report higher interstitial-fluid lactate in patients than in unaffected people; the cited comparison changes both the population and condition. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    Previous studies reported altered glucose metabolism, dysregulated lipid homeostasis, and lysosomal/autophagosomal impairments by ApoE4 in various cell types, including neurons and astrocytes.

    “altered glucose metabolism, dysregulated lipid homeostasis, and lysosomal/autophagosomal impairments by ApoE4 in various cell types, including neurons and astrocytes.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [4] Farmer, 2021, APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis, Mol. Neurodegener. source

      The Discussion (page unavailable) reports altered glucose metabolism in APOE4-expressing neurons and astrocytes. The Results section on single-cell sequencing also reports lower expression of mitochondrial beta-oxidation genes in E4 astrocytes, offering limited support for altered lipid metabolism. The passages do not establish dysregulated lipid homeostasis broadly, and a search for lysosomal, autophagosomal, and autophagy impairments found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] Qi, 2021, ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism, Cell Rep. source

      The Results sections on ApoE4 neurons and astrocytic fatty-acid degradation report altered glucose metabolism and lipid handling in both cell types (pages unavailable). The Results also discuss lipophagy in neuronal lipid-droplet turnover, but do not establish ApoE4-induced lysosomal or autophagosomal impairment; that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] Wu, 2018, Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer’s Disease Risk Reduction and Early Intervention, J. Neurosci. source

      The Abstract and Discussion report deficient glucose uptake and metabolism in ApoE4-expressing brains, and the Introduction associates ApoE4 with deregulated lipid metabolism. Our copy does not establish ApoE4-related lysosomal or autophagosomal impairment, or the full set of claimed effects in both neurons and astrocytes. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    High lactate levels were detected in the default network brain area and showed a strong correlation with the Aβ deposit area in AD brains.

    “High lactate levels were detected in the brain area, the so-called default network, a set of brain areas spontaneously coactivated across time in the resting state, and showed a strong correlation with the Aβ deposit area in AD brains.32”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Buckner, 2005, Molecular, Structural, and Functional Characterization of Alzheimer’s Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory, J. Neurosci. source

      The section “Amyloid deposition occurs in regions active during young adult default states” reports a strong spatial correlation between default activity in young adults and amyloid deposition in older adults with AD. It does not report detecting high lactate levels or correlating lactate with amyloid deposits. Page numbers are unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [33] van der Kant, 2020, Amyloid-β-independent regulators of tau pathology in Alzheimer disease, Nat. Rev. Neurosci. source

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

    Study design and conductcitation
    § Discussion

    NPC identity was validated by immunostaining with anti-SOX-2 and Nestin antibodies.

    “After validating the identity of NPCs by immunostaining with anti-SOX-2 and Nestin antibodies, they were further differentiated into astrocytes with Astrocyte Medium (ScienCell) as described previously.8”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] TCW, 2017, An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells, Stem Cell Rep. source

      The Experimental Procedures section on immunocytochemistry describes antibody staining generally, but does not identify SOX-2 or Nestin antibodies or say they validated NPC identity. Searches for SOX2, Nestin, and NPC validation found no such passage in our copy; the Results instead describe staining used to assess astrocyte differentiation. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion

    In the human brain, aerobic glycolysis is associated with the neuronal developmental stage and gradually decreases with age, whereas glucose usage for mitochondrial OXPHOS is relatively sustained.

    “In the human brain, aerobic glycolysis is associated with the neuronal developmental stage, which gradually decreases with age, whereas glucose usage for mitochondrial OXPHOS is relatively sustained.24”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Goyal, 2017, Loss of Brain Aerobic Glycolysis in Normal Human Aging, Cell Metab. source

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

    Findingown data
    § Results

    The m+5 and m+6 fractions of glucose-6-phosphate and fructose-6-phosphate are significantly reduced in ApoE4 astrocytes, suggesting impaired glucose uptake.

    “the m+5 and m+6 fractions of glucose-6-phosphate (Figure 1J) and fructose-6-phosphate (Figure S2A) were significantly reduced in ApoE4 astrocytes, suggesting the possibility of impaired glucose uptake”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    The fraction of m+3 lactate is increased in ApoE4 astrocytes compared with ApoE3 astrocytes, indicating enhanced aerobic glycolysis.

    “We observed an increased fraction of m+3 lactate in ApoE4 astrocytes compared with that in ApoE3 astrocytes, indicating enhanced aerobic glycolysis in these cells”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Glycolytic capacity and glycolytic reserve are increased in ApoE4 astrocytes compared with ApoE3 astrocytes.

    “Glycolytic capacity and glycolytic reserve, measured by sequential treatment with oligomycin and 2-deoxy-D-glucose (2-DG), were also shown to be increased in ApoE4 astrocytes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    ApoE4 astrocytes show impaired mitochondrial respiration or reduced OXPHOS compared with ApoE3 astrocytes.

    “The oxygen consumption rate assay showed a significantly reduced basal respiration rate in ApoE4 astrocytes compared with that in ApoE3 astrocytes”
    • Also stated in: § 6 Send email to gotra827@kiom.re.kr ∙ In-Kyu Lee · plain
      “Human ApoE4 astrocytes display increased glycolytic activity and reduced OXPHOS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Colocalization of lysosomes and mitochondria is significantly increased in ApoE4 astrocytes, suggesting impaired lysosome-dependent mitochondrial degradation.

    “The significantly increased colocalization of lysosomes and mitochondria found in ApoE4 astrocytes was likely due to lysosomal dysfunction, suggesting impaired lysosome-dependent mitochondrial degradation in these cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    ApoE4 astrocytes have increased autophagosomes (RFP and GFP) and decreased autolysosomes (RFP only) compared with ApoE3 astrocytes, indicating impaired autophagy flux.

    “We observed increased autophagosomes (RFP and GFP) and decreased autolysosomes (RFP only) in ApoE4 astrocytes compared with ApoE3 astrocytes, indicating impaired autophagy flux”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Results

    Glutamate treatment induces a transient increase in lactate levels in both ApoE3 and ApoE4 astrocytes.

    “We observed a transient increase in lactate levels in both ApoE3 and ApoE4 astrocytes upon glutamate treatment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    There is no difference in Aβ-induced lactate synthetic activity in ApoE4 astrocytes compared with ApoE3 astrocytes and no interaction effect between time and genotypes.

    “We did not observe the difference in Aβ-induced lactate synthetic activity in ApoE4 astrocytes compared with in ApoE3 astrocytes and the interaction effect between time and genotypes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    MβCD treatment restores autolysosomes and autophagosome areas in ApoE4 astrocytes, suggesting normalized autophagy flux.

    “We observed the restoration of autolysosomes and autophagosome areas in ApoE4 astrocytes with MβCD treatment, suggesting normalized autophagy flux”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Most transcripts of genes associated with OXPHOS are downregulated in ApoE4 astrocytes, while glycolysis genes are relatively equally up- or downregulated.

    “While a relatively equal number of genes involved in glycolysis were being either up- or downregulated, the transcripts of most of the genes associated with OXPHOS were downregulated”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Results

    Aβ-induced lactate synthesis tends to increase with time.

    “Unlike glutamate treatment, Aβ-induced lactate synthesis tends to increase with time.”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Discussion

    Increased circular forms of mitochondria in ApoE4 astrocytes observed by electron microscopy suggested accumulation of dysfunctional mitochondria.

    “Finally, while increased circular forms of mitochondria in ApoE4 astrocytes observed by electron microscopy suggested accumulation of dysfunctional mitochondria, it did not provide direct evidence of ApoE4-induced perturbation of mitochondrial biogenesis or turnover and its causal relationship with metabolic abnormality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    MβCD-treated ApoE4 astrocytes display a reduced LysoTracker area comparable to ApoE3 astrocytes without disrupting plasma membrane lipid integrity.

    “MβCD-treated ApoE4 astrocytes also displayed a reduced LysoTracker area in cells comparable to that in ApoE3 astrocytes without disrupting the integrity of the lipids on the plasma membrane measured by time-of-flight secondary ion mass spectrometry (ToF-SIMS)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In another ApoE3/ApoE4 isogenic astrocyte pair, ApoE4 astrocytes display impaired autophagy flux compared with isogenic ApoE3 cells, and this effect is attenuated by MβCD treatment.

    “As shown in Figures 3L–3O, ApoE4 astrocytes displayed impaired autophagy flux compared with their isogenic ApoE3 cells, and this effect was attenuated by MβCD treatment”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Discussion

    Proteomics of AD brains revealed strong upregulation of glial proteins associated with glucose metabolism.

    “Proteomics of AD brains revealed strong upregulation of glial proteins associated with glucose metabolism.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Johnson, 2020, APOE and metabolic dysfunction in Alzheimer’s disease, Int. Rev. Neurobiol. source

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

    Study design and conductnone given
    § Discussion

    Internal mass calibration for all ToF-SIMS spectra was conducted using the peaks of CH3+, Na+, C2H3+, C3H5+, and C27H45+ for the positive mode before further analysis.

    “Internal mass calibration for all the ToF-SIMS spectra was conducted using the peaks of CH3+, Na+, C2H3+, C3H5+, and C27H45+ for the positive mode before further analysis.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Discussion

    Extracellular acidification by enhanced glycolytic activity in ApoE4 astrocytes contributes to Aβ accumulation in the brain.

    “suggesting an additional contribution of extracellular acidification by enhanced glycolytic activity in ApoE4 astrocytes to Aβ accumulation in the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Su, 2001, Acidic pH promotes the formation of toxic fibrils from β-amyloid peptide, Brain Res. source

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

    Study design and conductnone given
    § Discussion

    Every batch of hiPSC-derived astrocytes was validated for resting state by treatment with immune stimuli such as polyinosinic-polycytidylic acid after serum deprivation.

    “Although every batch of hiPSC-derived astrocytes was subjected to the validation of their resting state by the treatment of immune stimuli such as polyinosinic-polycytidylic acid after serum deprivation, it is still possible that early exposure of astrocytes to serum induces the changes in the transcriptome, morphology, and function compared with those from cells that never encountered serum.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Discussion

    Inhibition of astrocyte-specific glycolysis or astrocyte-neuron lactate shuttles impairs long-term memory formation in mice.

    “Inhibition of astrocyte-specific glycolysis or astrocyte-neuron lactate shuttles was shown to impair long-term memory formation in mice.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Mächler, 2016, In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons, Cell Metab. source

  • May combine two claims.

    Interpretationown data
    § Discussion

    ApoE4 in astrocytes has detrimental effects on glucose metabolism and mitochondrial fitness, suggesting contributions of ApoE4 to AD pathogenesis and explaining the impact of ApoE4 on later stages of life.

    “Taken together, our study demonstrating the detrimental effects of astrocyte ApoE4 in glucose metabolism and mitochondria fitness suggests contributions of ApoE4 in AD pathogenesis and provides an explanation of the impact of ApoE4 on later stages of life.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Discussion

    Other adverse effects of disrupted lysosomal function by cholesterol could indirectly lead to mitochondrial dysfunction.

    “Lastly, although this study suggests that cholesterol-dependent mitophagy impairment causes mitochondrial dysfunction, it is possible that other adverse effects of disrupted lysosomal function by cholesterol could indirectly lead to mitochondrial dysfunction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given
    § Discussion

    Early exposure of astrocytes to serum may induce changes in transcriptome, morphology, and function compared with cells that never encountered serum.

    “Although every batch of hiPSC-derived astrocytes was subjected to the validation of their resting state by the treatment of immune stimuli such as polyinosinic-polycytidylic acid after serum deprivation, it is still possible that early exposure of astrocytes to serum induces the changes in the transcriptome, morphology, and function compared with those from cells that never encountered serum.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Discussion

    Cell number was measured with DAPI staining to normalize Seahorse values.

    “At the end of the experiment, cell number was measured with DAPI staining to normalize the value using ImageXpress Micro Confocal (Molecular Devices).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Discussion

    The bleed-through from mTFP to the long-band PMT was 0.45, and from Venus to the short-band PMT was 0.02, which was ignored.

    “The bleed-through from mTFP to the long-band PMT was 0.45, and from Venus to short-band PMT, it was 0.02, which was ignored.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Discussion

    All identified proteins in the proteomic analysis had a false discovery rate of ≤1%, calculated at the peptide level.

    “All identified proteins had a false discovery rate of ≤1%, which was calculated at the peptide level.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Discussion

    Mass spectrometer calibration was performed using the proposed calibration solution, according to the manufacturer's instructions.

    “Mass spectrometer calibration was performed using the proposed calibration solution, according to the manufacturer’s instructions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    Increased cholesterol levels could lead to lysosomal dysfunction and impaired mitochondrial homeostasis.

    “which could lead to lysosomal dysfunction and impaired mitochondrial homeostasis (Figure 5K).”
    Quote in the paperSubstantial claim
43 of 43

  • The paper relies on this without support.

    The causal relationship between ApoE4 and altered glucose metabolism, its underlying mechanisms, and its contribution to Alzheimer's disease pathogenesis remains elusive.

    “However, the causal relationship between ApoE4 and altered glucose metabolism, its underlying mechanisms, and its contribution to AD pathogenesis remains elusive.”

  • The paper relies on this without support.

    APOE4 is one of the strongest genetic risk factors for Alzheimer's disease.

    “Of the three isoforms (ε2, ε3, and ε4), ε4 (APOE4) is well known as one of the strongest genetic risk factors for AD.”

  • The paper relies on this without support.

    Accumulation of cholesterol in cells disrupts the function of intracellular membranous compartments, including lysosomes, which are important for the homeostasis of mitochondria.

    “This phenotypic abnormality is especially intriguing because the accumulation of cholesterol in cells disrupts the function of intracellular membranous compartments, including lysosomes, which are important for the homeostasis of mitochondria, essential organelles for energy metabolism.”

  • The authors state this as an assumption.

    The half-life of mitochondria in astrocytes is unknown.

    “although their half-life in astrocytes is unknown.”

  • The paper relies on this without support.

    ApoE4 greatly increases the risk of AD and lowers the age of onset.

    “ApoE4, which greatly increases the risk of AD and lowers the age of onset”

  • The paper relies on this without support.

    FBS in astrocyte culture media makes astrocytes more proliferative.

    “Because having FBS in astrocyte culture media was known to make astrocytes more proliferative”

  • The paper relies on this without support.

    Including serum in astrocyte culture media is critical for the proliferation of cells after differentiation from hiPSCs.

    “as including serum in astrocyte culture media is critical for the proliferation of cells after differentiation from hiPSCs”

  • The paper relies on this without support.

    Astrocytes transport lactate to neurons, and it is converted to pyruvate and subsequently oxidized to produce energy in response to neuronal activity.

    “Astrocytes transport lactate to neurons, and it is converted to pyruvate and subsequently oxidized to produce energy in response to neuronal activity.”
8 of 8

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?

  • This mitochondrial dysfunction partly results from a blockade of mitophagy owing to APOE4-mediated lysosomal dysfunction, leading to accumulation of damaged and dysfunctional mitochondria in APOE4 carriers.

    “in vitro studies have indicated that this mitochondrial dysfunction partly results from a blockade of mitophagy owing to APOE4-mediated lysosomal dysfunction, which leads to an accumulation of damaged and dysfunctional mitochondrial in APOE4 carriers167–169.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [169]

    The Results and Discussion (pages unavailable) link ApoE4-related lysosomal dysfunction to impaired mitochondrial degradation and accumulation of dysfunctional mitochondria in cultured human astrocytes. The Discussion describes mitophagy impairment as a suggested mechanism and says the study did not directly establish altered mitochondrial turnover. The claim extends this finding to APOE4 carriers generally and presents a mitophagy blockade more definitively than the paper does. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of Alzheimer's disease.

    “Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of AD [16, 17, 18].”

    From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [18]

    The Introduction and Discussion report dysfunctional mitochondria in ApoE4 human astrocytes and suggest that these changes contribute to AD pathogenesis. They do not report that mitochondrial damage causes lipid-droplet accumulation or that such droplets further exacerbate AD progression; the causal pathway studied instead runs from lysosomal cholesterol accumulation to impaired removal of damaged mitochondria. No page numbers are available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The decrease in PDH subunits and increase in PC in APOE4 iAstrocytes is consistent with a previous study.

    “Surprisingly, we saw differences in these proteins including a decrease in subunits of PDH and an increase in PC in APOE4 iAstrocytes consistent with a previous study 35 .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [35]

    The Results (page unavailable) report enhanced aerobic glycolysis and impaired mitochondrial respiration in ApoE4 astrocytes, broadly consistent with altered glucose metabolism. They do not report decreased PDH subunits or increased PC; searches for PDH and pyruvate carboxylase found no such comparison. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Some studies found that APOE4 reduced glycolysis, whereas others observed a shift from oxidative to glycolytic metabolism in APOE4 cells with higher glycolytic activity in APOE4 than APOE3.

    “Some studies found that APOE4 reduced glycolysis [28,39], whereas others observed a shift from oxidative to glycolytic metabolism in APOE4 cells with higher glycolytic activity in APOE4 than APOE3 [40,41,42].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [40]

  • These findings of decreased mitochondrial function and a switch to glycolysis are consistent with previous studies.

    “These findings of decreased mitochondrial function and a switch to glycolysis is consistent with previous studies 33,35 .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [35]

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Authors
Lee, H., Cho, S., Kim, M.-J., Park, Y. J., Cho, E., Jo, Y. S., Kim, Y.-S., Lee, J. Y., Thoudam, T., Woo, S.-H., Lee, S.-I., Jeon, J., Lee, Y.-S., Suh, B.-C., Yoon, J. H., Go, Y., Lee, I.-K., & Seo, J.
Affiliations
  • Daegu Gyeongbuk Institute of Science and Technology (KR)
  • Kyungpook National University (KR)
  • Korea Institute of Oriental Medicine (KR)
  • Korea Brain Research Institute (KR)
Corresponding author
  • Go, Younghoon
  • Lee, In-Kyu
  • Seo, Jinsoo
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-10
Volume
42
Issue
10
Pages
113183
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.113183
OpenAlex
W4387207575
Cited by
93
References
45
Citations by year
2026: 36 · 2025: 38 · 2024: 19
FWCI
16.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Korea Health Industry Development Institute
  • Korea Institute of Oriental Medicine (KSN2022230)
  • Massachusetts Institute of Technology
  • National Research Foundation of Korea (2018M3C7A1056275, 2022R1A2B5B03001929)
  • Korea Brain Research Institute
  • Daegu Gyeongbuk Institute of Science and Technology (22-CoE-BT-01)
  • Ministry of Health and Welfare (21-BR-03-02, HU21C0111)
  • Ministry of Science, ICT and Future Planning (22-BR-02-03)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
APOE ε4, lysosomal cholesterol accumulation, astrocytes, mitochondrial homeostasis, oxidative phosphorylation, autophagy, mitochondrial respiration, mitochondrial dynamics, glycolysis, cholesterol depletion, Alzheimer's disease, induced pluripotent stem cell-derived astrocytes
MeSH terms
Alzheimer Disease, Apolipoproteins E, Astrocytes, Cells, Cultured, Cholesterol, Humans, Oxidative Phosphorylation, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

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

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