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Cited by 539Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsLipid metabolism and biosynthesis

APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia

Open access
Haney, Michael S., Pálovics, Róbert, Munson, Christy Nicole, Long, Chris, Johansson, Patrik K., Yip, Oscar, Dong, Wentao, Rawat, Eshaan +20 more·2024·Nature
DOI 10.1038/s41586-024-07185-7PMC PMC10990924
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Abstract

Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells 1 . However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.

AI snapshot

Written from the paper’s full text.

TL;DR

Single-nucleus RNA sequencing of human Alzheimer’s disease brain identifies an ACSL1+ lipid-droplet-accumulating microglial state (LDAM) that is most abundant in APOE4/4 AD. In iPS-derived microglia, fibrillar Aβ induces ACSL1, triglyceride synthesis, and lipid droplets in an APOE-dependent manner, and conditioned media from lipid-droplet-high microglia induce Tau phosphorylation and neurotoxicity.

Key findings

  • snRNA-seq of frontal cortex yielded ~100,000 single-nucleus transcriptomes (n = 100,317 cells); ACSL1 was the most significantly differentially expressed gene in AD-APOE4/4 versus control microglia. ACSL1+ LDAM were a distinct state from homeostatic and DAM microglia, with the greatest percentage in AD-APOE4/4, followed by AD-APOE3/3, and least in age-matched controls (chi-square P < 0.0001); immunofluorescence confirmed ACSL1 abundance differences (n = 5 per group).
  • Oil Red O+ neutral lipid bodies were abundant in AD-APOE4/4 brain tissue, often near or at Aβ plaques, with a slight but not significant increase in AD-APOE4/4 versus AD-APOE3/3 (control n = 12; AD33 n = 7; AD44 n = 9). Lipid body counts negatively correlated with MMSE and positively correlated with Aβ plaque amounts and Tau pathology; microglial ACSL1 expression positively correlated with lipid body numbers. J20/APOE3 and J20/APOE4 mice had more LD+ microglia than age-matched wild-type mice (n = 3 mice per group).
  • In isogenic APOE4/4 versus APOE3/3 iMG, fibrillar Aβ strongly increased lipid droplet accumulation, exacerbated by APOE4 and absent in APOE-KO; fAβ upregulated PLIN2 and ACSL1. CARS spectra overlapped unsaturated/triglyceride spectra, and d-glucose 13C incorporation into triglycerides increased time-dependently after fAβ. CRISPR screens identified triglyceride metabolism regulators and ACSL1 as required for LD formation; the top druggable-genome hit in APOE4/4 iMG was PIK3CA, and ACSL1 inhibitor Triacin C or PI3K inhibitor GNE-317 reduced lipid droplets.
  • Conditioned media from LD-high APOE4/4 iMG induced high pTau (AT8) and caspase activation in human iPS cell-derived neurons; effects were similar with APOE3/3 and APOE4/4 iMG-conditioned media but absent with APOE-KO iMG-conditioned media. Neurons exposed to LD-high conditioned media showed increased LipidSpot staining and higher concentrations of triglyceride lipid species.

Methods

  • Human postmortem frontal cortex from AD-APOE4/4, AD-APOE3/3, and age/sex-matched control APOE3/3 individuals was processed for snRNA-seq (~100,000 nuclei), with CellRanger alignment, Scanpy/BBKNN integration, Leiden clustering, pseudobulk DESeq2, and MAST single-cell differential expression; microglia were subclustered and annotated using HOMEOSTATIC, DAM, and LDAM marker signatures.
  • Histology and imaging included Oil Red O, immunofluorescence for IBA1/ACSL1/Aβ in human tissue, and IBA1/LipidSpot imaging in J20/APOE3-KI and J20/APOE4-KI mice. Cell models included isogenic APOE3/3, APOE4/4, and APOE-KO iPS cell-derived microglia, iPS cell-derived human neurons, primary rat microglia, BV2 cells, and human macrophages; assays included fAβ treatment, live-cell microscopy, CARS, electron microscopy, lipidomics, cytokine/chemokine assays, ATAC-seq, and RNA-seq.
  • CRISPR–Cas9 screens were performed genome-wide in U937 cells and with a druggable-genome library in APOE4/4 iMG, using FACS for LD-high versus LD-low populations and casTLE analysis. Conditioned media from FACS-sorted LD-high and LD-low iMG were applied to iPS cell-derived neurons, followed by AT8 and cleaved caspase-3 quantification.

Limitations

  • The paper states that identifying the cell type(s) accumulating lipids requires simultaneous staining for lipids and several protein markers, which is challenging in aged human histological brain sections; that GNE-317 experiments do not conclusively show increased autophagic flux; and that 13C-labelled TAG lipids in mouse neurons treated with conditioned media were not robustly detected across several replicates, perhaps due to low isotopic enrichment.
  • Evident from the text: human postmortem associations are cross-sectional and correlational, and several experiments rely on small samples (for example, n = 3 mice per group and n = 3 replicate wells in multiple assays). The mechanistic work largely uses in vitro iPS cell-derived microglia/neurons and mouse models, which may not fully capture human AD.

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

Integrity signals

Registry

Crossref · 10.1038/s41586-024-07185-7

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

30 of 44 cited sources checked · 19 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    Gene expression of lipid droplet-associated genes PLIN2 and ACSL1 is upregulated on fibrillar Aβ challenge in iMGs.

    “In accordance with this accumulation of LDs, the gene expressions of LD-associated genes PLIN2 (ref. 21) and ACSL1 (refs. 13,14) are upregulated on fAβ challenge in iMGs”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [21] Olzmann, J. A. & Carvalho, P. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 20, 137–155 (2019). source

      The citation is attached to ACSL1’s identification as a lipid-droplet-associated gene. The lipid droplet–lysosome contacts section discusses PLIN2, but the passages found for ACSL1 do not establish that association. The source also does not report gene-expression changes after fibrillar Aβ challenge in iMGs. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [13] Li, L. O. et al. Overexpression of rat long chain acyl-coa synthetase 1 alters fatty acid metabolism in rat primary hepatocytes. J. Biol. Chem. 281, 37246–37255 (2006). source
    • cites [14] Zhao, Z. et al. Effects of overexpression of ACSL1 gene on the synthesis of unsaturated fatty acids in adipocytes of bovine. Arch. Biochem. Biophys. 695, 108648 (2020). source
  • Premisecitation

    LDAM were also observed in chimaeric human-mouse Alzheimer's disease models.

    “LDAM were also observed in chimaeric human–mouse AD models6.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Claes, C. et al. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease. Mol. Neurodegener. 16, 50 (2021). source
  • Findingown data

    Live cell microscopy showed greater lipid droplet accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG.

    “Live cell microscopy of iMG with a fluorescent dye for neutral lipids (LipidSpot) showed greater LD accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG, similar to recent reports in isogenic iMG4 and astrocytes20.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [4] Victor, M. B. et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell 29, 1197–1212 (2022). source
    • cites [20] Sienski, G. et al. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci. Transl. Med. 13, eaaz4564 (2021). source
  • Premisecitation

    Human induced pluripotent stem cell-derived microglia with APOE risk variants have more lipid droplets.

    “human induced pluripotent stem (iPS) cell-derived microglia (iMG) with APOE risk variants have more lipid droplets (LDs)4.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Victor, M. B. et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell 29, 1197–1212 (2022). source
  • Findingcitation

    There are more lipid-droplet-positive microglia in J20/APOE3 and J20/APOE4 Alzheimer's disease mouse models compared to age-matched wild-type mice.

    “Mirroring these observations in the human AD tissue, there are more LD+ microglia in the J20/APOE3 and J20/APOE4 models of AD15 compared to age-matched wild-type mice”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Taubes, A. et al. Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease. Nat. Aging 1, 932–947 (2021). source

      The Methods (Mice; page unavailable) identify J20/E3-KI, J20/E4-KI, and wild-type mice. The Results on J20/E4-KI neurons and glia discuss microglial gene expression, but neither passage reports counts of lipid-droplet-positive microglia compared with age-matched wild-type mice. Searches for “lipid droplets,” “LD+ microglia,” and the model comparison found no passage addressing that outcome. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 40

  • May combine two claims.

    Premisecitation

    This epigenetic signature is also seen in macrophages in atherosclerosis models and adipose-associated macrophages, but this signature is not seen in DAM microglia.

    “This epigenetic signature is also seen in macrophages in atherosclerosis models23 and adipose-associated macrophages24 but this signature is not seen in DAM microglia25.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [23] Xiong, X., Yan, Z., Jiang, W. & Jiang, X. ETS variant transcription factor 6 enhances oxidized low-density lipoprotein-induced inflammatory response in atherosclerotic macrophages via activating NF-κB signaling. Int. J. Immunopathol. Pharmacol. https://doi.org/10.1177/20587384221076472 (2022). source

      The Results section ('Elevation of ETV6 in aorta macrophages in ApoE−/− mice'; page unavailable) reports increased ETV6 expression in macrophages from an atherosclerosis model. The cited portion of the sentence concerns an epigenetic signature, but neither that section nor the passages retrieved by searching for epigenetic and chromatin terms identifies or measures one. The adipose-macrophage and DAM-microglia portions have separate citations and are not assessed here. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [24] Hill, D. A. et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc. Natl Acad. Sci. USA 115, E5096–E5105 (2018). source
    • cites [25] Morabito, S. et al. Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease. Nat. Genet. 53, 1143–1155 (2021). source

      The Results section on the microglia trajectory reports depletion of a stage 2 DAM gene signature, but does not identify the epigenetic signature meant by the citing sentence or say that it is absent in DAM microglia. Searches for that epigenetic signature and for a comparison with macrophages did not find a passage establishing the cited claim; page numbers were unavailable in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A previously published dataset shows that ACSL1 is highly upregulated by the innate immune trigger lipopolysaccharides in an independent human iMG chimaeric mouse model.

    “A previously published dataset shows that ACSL1 is highly upregulated by the innate immune trigger lipopolysaccharides (LPS) in an independent human iMG chimaeric mouse model22”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Hasselmann, J. et al. Development of a chimeric model to study and manipulate human microglia in vivo. Neuron 103, 1016–1033 (2019). source

      The Results section, “xMGs respond robustly to a systemic inflammatory challenge” (page not available), reports a dataset comparing human microglia from saline- and LPS-treated chimeric mice and identifies 607 upregulated genes. Our copy does not identify ACSL1 among them or establish that it was highly upregulated; searches for ACSL1 and its full gene name found no supporting passage. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    APOE is a lipid-related Alzheimer's disease risk gene and is highly upregulated in human microglia in Alzheimer's disease.

    “APOE is one such lipid-related AD risk gene, which is highly upregulated in human microglia in AD3”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source

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

    Premisecitation

    Lipid droplets form in myeloid cells through upregulation of lipid-synthesis enzymes triggered by engagement of toll receptors by innate immune triggers such as bacteria.

    “LDs form in myeloid cells through the upregulation of lipid-synthesis enzymes triggered by the engagement of toll receptors by innate immune triggers, such as bacteria7.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Huang, Y. et al. Toll-like receptor agonists promote prolonged triglyceride storage in macrophages. J. Biol. Chem. 289, 3001–3012 (2014). source

      The Discussion reports that TLR agonists increased triglyceride synthesis and the abundance of ACSL1 and DGAT2 in macrophages, supporting the proposed link to lipid droplets. But it describes enzyme upregulation as one part of a multifaceted storage response, alongside increased fatty-acid uptake and decreased lipolysis; it does not establish this as the mechanism across myeloid cells generally. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Aged mouse microglia accumulate lipid droplets and exhibit a dysfunctional microglial state termed lipid-droplet-accumulating microglia (LDAM).

    “Aged mouse microglia accumulate LDs and exhibit a dysfunctional microglial state termed LD-accumulating microglia (LDAM)5”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Marschallinger, J. et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194–208 (2020). source

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

    Premisecitation

    Cholesterol-rich lysosomes and lipid droplets in dysfunctional microglia have been observed in demyelination mouse models and human iPS cell models.

    “Cholesterol-rich lysosomes and LDs in dysfunctional microglia have also been observed in the context of demyelination mouse models and human iPS cell models9–12.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [9] Safaiyan, S. et al. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995–998 (2016). source

      The passage on Pelizaeus–Merzbacher disease mice (page unavailable in our copy) reports demyelination, increased lipofuscin in microglia, and reduced microglial uptake function. The paper also describes lipofuscin as accumulating in lysosomes. It does not identify those lysosomes as cholesterol-rich or report lipid droplets or human iPS-cell models. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] Cantuti-Castelvetri, L. et al. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359, 684–688 (2018). source

      The main text (p. 1) reports myelin debris in phagocyte lysosomes and lipid-droplet-bearing foam cells in demyelinated old mice; the supplementary Fig. 3 caption (p. 6) identifies microglial cultures treated with myelin debris. Our copy does not report these observations in human iPS cell models, so it supports the mouse-model portion but not that extension. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [11] Nugent, A. A. et al. TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron 105, 837–854 (2020). source
    • cites [12] Tcw, J. et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell 185, 2213–2233 (2022). source

      The Results (‘Altered lipid metabolism in human APOE4 microglia and astrocytes’; page unavailable) report impaired cholesterol metabolism in human iPSC-derived microglia and predict lysosomal cholesterol accumulation. They do not establish cholesterol-rich lysosomes or lipid droplets in those microglia, or report those observations in demyelination mouse models. The measured increase in lysosomal cholesterol described in ‘Impaired cholesterol trafficking’ was in astrocytes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Autophagy is known to regulate lipid droplet concentrations.

    “a mechanism which is known to regulate LD concentrations27–29”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [27] Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009). source
    • cites [28] Qiao, L. et al. Deficient chaperone-mediated autophagy promotes lipid accumulation in macrophage. J. Cardiovasc. Transl. Res. 14, 661–669 (2021). source
    • cites [29] Zhou, H. et al. In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice. Nat. Neurosci. 21, 440–446 (2018). source

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

    Premisecitation

    Mouse LDAM have a dysfunctional and inflammatory microglial state.

    “These results are similar to recent reports describing mouse LDAM that have a dysfunctional and inflammatory microglial state5.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Marschallinger, J. et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194–208 (2020). source

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

    Premisecitation

    PI3 kinase inhibition is a known modulator of lipid droplets in mouse macrophages, but this has not been previously shown in human microglia.

    “PI3 kinase inhibition is a known modulator of LDs in mouse macrophages26 but this has not been previously shown in human microglia.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] Pacheco, P. et al. Monocyte chemoattractant protein-1/CC chemokine ligand 2 controls microtubule-driven biogenesis and leukotriene B 4-synthesizing function of macrophage lipid bodies elicited by innate immune response. J. Immunol. 179, 8500–8508 (2007). source

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

    Premisecitation

    Lipid-laden foamy macrophages in atherosclerosis have a senescent phenotype and are drivers of pathology.

    “lipid-laden ‘foamy macrophages’ in atherosclerosis which have a senescent phenotype and are drivers of pathology37.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Isogenic APOE4/4 and APOE3/3 iPS cells were used.

    “Isogenic APOE4/4 and APOE3/3 iPS cells were generated as previously described16.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector article. Nat. Med. 24, 647–657 (2018). source

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

    Study design and conductcitation

    BBKNN was used to integrate data across samples and correct for potential sample-wise batch effects.

    “We then used the Python implementation of BBKNN (v.1.5.1), a fast batch correction algorithm suitable for large datasets to integrate data across the samples45. BBKNN calculates a batch-corrected neighbourhood graph from the imputed principal components. We set the individual sample IDs as batch labels to correct for potential sample-wise batch effects.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Polański, K. et al. BBKNN: fast batch alignment of single cell transcriptomes. Bioinformatics 36, 964–965 (2020). source

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

    Premisecitation

    Alpha-synuclein binding to TLR2 and TLR5 induces microglial NLRP3 inflammasome activation, which is a shared signature seen in LDAM.

    “alpha-synuclein binding to TLR2 and TLR5 induces microglial NLRP3 inflammasome activation, which is a shared signature seen in LDAM36.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Scheiblich, H. et al. Microglial NLRP3 inflammasome activation upon TLR2 and TLR5 ligation by distinct α-synuclein assemblies. J. Immunol. 207, 2143–2154 (2021). source

      The Discussion (page not available) reports that α-synuclein monomers and oligomers act through TLR2 to prime the microglial NLRP3 inflammasome and through TLR5 to activate it. The paper does not identify this activation as a shared signature of LDAM; searches for LDAM and lipid-droplet-associated microglia found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Recent work shows deleterious effects of conditioned media on neurons from astrocytes and microglia.

    “This approach takes inspiration from recent work showing the deleterious effects of conditioned media on neurons from astrocytes30 and microglia4.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [30] Guttenplan, K. A. et al. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature 599, 102–107 (2021). source
    • cites [4] Victor, M. B. et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell 29, 1197–1212 (2022). source

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

    Study design and conductcitation

    Doublets were removed from snRNA-seq data using Scrublet with sample-specific thresholds.

    “Count data were first screened for doublets with the Scrublet (v.0.2.3) Python package43. Once each cell was doublet scored, we applied a separate doublet score threshold per sample to discard doublets from the data.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Wolock, S. L., Lopez, R. & Klein, A. M. Scrublet: computational identification of cell doublets in single-cell transcriptomic data. Cell Syst. 8, 281–291 (2019). source

  • May combine two claims.

    Findingown data

    AD-APOE4/4 brain tissue has the greatest percentage of LDAM, followed by AD-APOE3/3, with the least LDAM microglia state in age-matched control brain tissue.

    “AD-APOE4/4 brain tissue has the greatest percentage of LDAM, followed by AD-APOE3/3 and the least amount of the LDAM microglia state is found in the aged-matched control brain tissue”
    • Also stated in: § Discussion · plain
      “We report that LDAM are more prevalent in AD brains compared to controls and enriched in individuals with the APOE4/4 genotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A genome-wide CRISPR-KO screen in U937 cells revealed regulators of triglyceride metabolism as a top category of genes required for lipid droplet accumulation and ACSL1 as one of the most significant genes required for lipid droplet formation.

    “This screen revealed regulators of triglyceride metabolism as being a top category of genes required for LD accumulation and ACSL1 as one of the most significant genes required for LD formation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In single-nucleus RNA sequencing of Alzheimer's disease brain tissue, a microglial state defined by expression of the lipid droplet-associated enzyme ACSL1 was identified, and ACSL1-positive microglia were most abundant in patients with Alzheimer's disease having the APOE4/4 genotype.

    “Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4 genotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ACSL1 was upregulated specifically in microglia in Alzheimer's disease brain tissue compared to controls, and to a greater extent in APOE4/4 compared to AD-APOE3/3 microglia.

    “ACSL1 was upregulated specifically in microglia in AD brain tissue compared to controls and to a greater extent in APOE4/4 compared to AD-APOE3/3 microglia”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The number of lipid bodies is negatively correlated with cognitive performance as measured by the mini-mental state exam and positively correlated with amyloid-β plaque amounts and Tau pathology levels.

    “The number of lipid bodies is negatively correlated with cognitive performance, as measured by the mini-mental state exam (MMSE) and positively correlated with Aβ plaque amounts and Tau pathology levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of iMG with fibrillar Aβ led to a strong increase in lipid droplet accumulation, which was exacerbated by the presence of the APOE4 Alzheimer's disease risk allele.

    “However, treatment of iMG with fibrillar Aβ (fAβ) led to a strong increase in LD accumulation which was exacerbated by the presence of the APOE4 AD-risk allele.”
    • Also stated in: § Discussion · plain
      “We also describe the induction of triglyceride synthesis and LD accumulation following fAβ treatment in iMG and that the LD induction is greater in isogenic APOE4/4 iMG than APOE3/3 iMG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lipid bodies are most prevalent in Alzheimer's disease brain tissue, with a slight but not significant increase in AD-APOE4/4 compared to AD-APOE3/3.

    “These lipid bodies are most prevalent in AD brain tissue with a slight but not significant increase in individuals with AD-APOE4/4 compared to those with AD-APOE3/3”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingown data

    Single-nucleus RNA sequencing yielded approximately 100,000 single-nucleus transcriptomes with all main cell types of the brain represented.

    “This yielded ~100,000 single-nucleus transcriptomes with all main cell types of the brain represented”
    Quote in the paperSubstantial claim

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

    Findingown data

    13C-labelled TAG lipids synthesized in microglia were observed in mouse neurons treated with conditioned media from BV2s grown in 13C-labelled glucose, but this was not robustly detected across several replicates.

    “13C-labelled TAG lipids synthesized in microglia were also observed in mouse neurons treated with conditioned media from BV2s grown in 13C-labelled glucose, however, this was not robustly detected across several replicates perhaps due to the low isotopic enrichment of these lipids”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The LDAM expression signature, such as ACSL1 and NAMPT upregulation, is unique to microglia.

    “the LDAM expression signature, such as ACSL1 and NAMPT upregulation, seems to be unique to microglia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Phenotypic measurements indicate that LD-containing APOE4/4 iMGs are dysfunctional in phagocytosis, accumulate lysosomes, and secrete inflammation-associated chemokines.

    “In accordance with these RNA-seq results, phenotypic measurements of LD-containing APOE4/4 iMGs indicate that they are dysfunctional in phagocytosis, accumulate lysosomes and secrete inflammation-associated chemokines as measured in the cell culture media”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RNA-seq indicated that LD-high microglia had higher expression of NF-κB-associated pro-inflammatory cytokines, for example TNFA and IL1B, and lower expression of microglial homeostasis markers compared to LD-low microglia.

    “RNA-seq results indicated that LD-high microglia had higher expression of NF-κB associated pro-inflammatory cytokines (for example, TNFA and IL1B) and lower expression of microglial homeostasis markers compared to LD-low microglia”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On GNE-317 treatment, genes in the PI3K/mTOR and autophagy pathways changed expression and LC3B protein levels increased.

    “On GNE-317 treatment, genes in the PI3K/mTOR and autophagy pathways exhibit changes in expression and we also observed an increase in LC3B protein levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Conditioned media from APOE3/3 and APOE4/4 iMGs with higher concentrations of lipid droplets induced caspase activation in human neurons, whereas conditioned media from APOE-KO iMG had no effect.

    “Likewise, conditioned media from APOE3/3 and APOE4/4 iMGs with a higher concentrations of LDs induced caspase activation in human neurons, whereas conditioned media from APOE-KO iMG had no effect”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only LD-high iMG-conditioned media induced high concentrations of phosphorylated Tau in iPS cell-derived neurons, whereas LD-low iMG-conditioned media induced phosphorylated Tau concentrations similar to the untreated condition.

    “Only the LD-high iMG-conditioned media induced high concentrations of pTau in the iPS cell-derived neurons, whereas the LD-low iMG-conditioned media induced similar concentrations of pTau in the iPS cell-derived neurons as the untreated condition”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The phosphorylated Tau induction effect was similar with conditioned media from APOE3/3 and APOE4/4 iPS cell-derived iMG but absent with conditioned media from APOE-KO iMGs.

    “This effect was similar when conditioned media from APOE3/3 and APOE4/4 iPS cell-derived iMG were used to treat the human neurons but absent when conditioned media from APOE-KO iMGs were used”
    Quote in the paperSubstantial claim

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

    Findingown data

    The second top hit from the CRISPR-KO screen was S100A1.

    “Interestingly, the second top hit was S100A1, an AD risk gene downstream of the LPS and TLR4 response in macrophages.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Lipid droplets have antimicrobial properties and are an evolutionarily conserved form of innate immune defence in macrophages.

    “LDs themselves have antimicrobial properties and are an evolutionarily conserved form of innate immune defence in macrophages8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Bosch, M. et al. Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense. Science 370, eaay8085 (2020). source

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

    Interpretationreasoning

    Cells containing lipid bodies near plaques could be ACSL1+ microglia.

    “suggesting that the cells containing lipid bodies near plaques could be ACSL1+ microglia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ACSL1 is a key enzyme in lipid droplet biogenesis, and its overexpression is sufficient to induce triglyceride-specific lipid droplet formation in several cell types.

    “ACSL1 is a key enzyme in LD biogenesis and overexpression of ACSL1 is sufficient to induce triglyceride-specific LD formation in several cell types13,14”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Li, L. O. et al. Overexpression of rat long chain acyl-coa synthetase 1 alters fatty acid metabolism in rat primary hepatocytes. J. Biol. Chem. 281, 37246–37255 (2006). source
    • cites [14] Zhao, Z. et al. Effects of overexpression of ACSL1 gene on the synthesis of unsaturated fatty acids in adipocytes of bovine. Arch. Biochem. Biophys. 695, 108648 (2020). source

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

    Study design and conductown data

    Cells with fewer than 500 genes, fewer than 1,000 reads, more than 10% mitochondrial reads, or more than 10% ribosomal reads were discarded.

    “We used the Scanpy (v.1.9.1) package to discard cells with (1) fewer than 500 genes or (2) less than total 1,000 reads or (3) more than 10% mitochondrial reads or (4) more than 10% ribosomal reads.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Microglia were subsampled with purification to conduct unbiased single-cell level downstream analysis not biased towards any patient samples.

    “To conduct unbiased single-cell level downstream analysis of the microglial cells which is not biased towards any of the patient samples, first we subsampled the microglia cluster with purification50.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Palovics, R., Wyss-Coray, T. & Mirzasoleiman, B. Purification of single-cell transcriptomics data with coreset selection. In The 2022 ICML Workshop on Computational Biology Paper 67 (ICML, 2022).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    Irreproducible discovery rate (IDR) was used to test for reproducibility between ATAC-seq replicates.

    “Irreproducible discovery rate (IDR) was used to test for reproducibility between replicates.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The iMG CRISPR-Cas9 screens were performed in duplicate culture conditions.

    “In duplicate culture conditions, cells were treated with 5 μM Aβ fibrils for 24 h, stained with BODIPY 493/503 (1:2,000 from 1 mg ml−1 of stock solution in DMSO; Thermo Fisher) and top 10% highest and 10% lowest BODIPY fluorescent cells were separated by FACS (Sony, MA900).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Hyperactive neurons can release APOE-associated fatty acids that are taken up by astrocytes and buffer lipotoxic stress.

    “cell culture models have demonstrated that hyperactive neurons can release APOE-associated fatty acids which are taken up by astrocytes and buffer lipotoxic stress35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Ioannou, M. S. et al. Neuron–astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177, 1522–1535 (2019). source

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

    Study design and conductnone given

    Cells were identified by thresholding with the Triangle method.

    “Cells were identified by thresholding with the Triangle method.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    ATAC-seq experiments were performed in replicate.

    “ATAC-seq experiments were performed in replicate and peaks were called with parameters -L 0 -C 0 -fdr 0.9 -minDist 200 -size 200.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Innate immune triggers (e.g., Escherichia coli and Salmonella) induce lipid droplet formation in peripheral macrophages as part of an evolutionarily conserved antimicrobial defence in which LDs coated with antimicrobial proteins such as cathelicidin (CAMP) kill bacteria.

    “A recent report showed that innate immune triggers (for example, Escherichia coli and Salmonella) induce LD formation in peripheral macrophages as part of an evolutionarily conserved antimicrobial defence in which LDs coated with antimicrobial proteins, such as cathelicidin (CAMP), kill bacteria8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Bosch, M. et al. Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense. Science 370, eaay8085 (2020). source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    P values were corrected with the Benjamini-Hochberg procedure (FDR = 0.05) per comparison.

    “P values were corrected with Benjamini–Hochberg procedure49 (false discovery rate (FDR) = 0.05) per comparison.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995). source

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

    Study design and conductown data

    The genome-wide lipid droplet CRISPR-Cas9 screens in U937 cells were performed in duplicate.

    “Screens were performed in duplicate.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Enhancing autophagy has previously been explored as a strategy to modulate neurodegeneration disease progression but with a focus on autophagic degradation of proteins, as opposed to autophagic degradation of intracellular LDs (lipophagy).

    “Enhancing autophagy has previously been explored as a strategy to modulate neurodegeneration disease progression but with a focus on autophagic degradation of proteins41, as opposed to the autophagic degradation of intracellular LDs (lipophagy).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Heras-Sandoval, D., Pérez-Rojas, J. M., Hernández-Damián, J. & Pedraza-Chaverri, J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell. Signal. 26, 2694–2701 (2014). source

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

    Study design and conductown data

    These experiments do not conclusively demonstrate increased autophagic flux of lipids in this context.

    “these experiments do not conclusively demonstrate that there is increased autophagic flux of lipids in this context”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    APOE genotype likely contributes to AD pathogenesis through several distinct mechanisms unique to individual cell-type dysfunction or through crosstalk between these cell types.

    “It is likely that the APOE genotype contributes to AD pathogenesis through several distinct mechanisms unique to individual cell-type dysfunction or through crosstalk between these cell types.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All assays were performed under serum-free conditions.

    “All assays were performed under serum-free conditions (MGdM media).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For all image analyses, a standard threshold value was chosen and automatically applied to each channel of each image before measurement.

    “For all image analyses, a standard threshold value was chosen and automatically applied to each channel of each image before measurement.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    In single-cell differential gene expression analysis, gender, expired age, postmortem interval, and percentage of mitochondrial and ribosomal counts were set as covariates.

    “We set gender, expired age, postmortem interval and the percentage of mitochondrial and ribosomal counts as covariates.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Intracellular lipid features were quantified using the '3D Objects Counter' command.

    “Intracellular lipid features were quantified using the ‘3D Objects Counter’ command.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    CAMP is found on lipid droplet surfaces with antimicrobial properties in macrophages exposed to bacteria.

    “which is found on LD surfaces with antimicrobial properties in macrophages exposed to bacteria8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Bosch, M. et al. Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense. Science 370, eaay8085 (2020). source

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

    Study design and conductnone given

    CARS stacks underwent east shadows correction, Gaussian blur filtering, and background subtraction.

    “The CARS stacks underwent east shadows correction, Gaussian blur filtering (σ = 1) and background subtraction (30 pixel rolling ball radius).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Lipid particles were identified by thresholding using FindFoci with specified parameters.

    “Lipid particles were identified by thresholding using the FindFoci method, with a search parameter for half peak value of 0.1, peak parameter for minimum peak height relative to background of 0 and a minimum peak size of 200 pixels.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    For each time point, red and green fluorescence was normalized to phase confluence per well.

    “For each time point, red and green fluorescence was normalized to the phase confluence per well.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    PI3K inhibition increases autophagy.

    “PI3K inhibition, shown to increase autophagy38.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Ersahin, T., Tuncbag, N. & Cetin-Atalay, R. The PI3K/AKT/mTOR interactive pathway. Mol. Biosyst. 11, 1946–1954 (2015). source
57 of 57

  • The paper relies on this without support.

    The relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood.

    “However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood.”

  • The paper relies on this without support.

    The role lipids and innate immunity play in Alzheimer’s disease risk remains poorly understood.

    “However, the role lipids and innate immunity play in AD risk remains poorly understood.”

  • The paper relies on this without support.

    Human induced pluripotent stem cell-derived microglia and neurons are valid models of human Alzheimer’s disease microglia and neurons.

    “APOE4/4 and isogenic APOE3/3 iPS cells16 were differentiated into microglia (iMG) as previously described17–19”

  • The paper relies on this without support.

    The LDAM state is maladaptive and damaging.

    “maladaptive and damaging LDAM state”

  • The paper relies on this without support.

    The iPS cell-derived microglia model recapitulates key aspects of human microglial biology relevant to LDAM.

    “Differentiation into microglia was performed as previously described17–19.”
5 of 5

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?

  • APOE4-associated glial LD accumulation modulates neuron function and brain memory.

    “and the APOE4-associated glial LD accumulation modulates neuron function and brain memory17–19.”

    From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [19]

    The ‘ACSL1 and triglycerides increase after fAβ challenge’ section reports greater lipid-droplet accumulation in APOE4/4 microglia. The ‘LD+ iMG induce pTau and apoptosis in neurons’ section reports that conditioned media from lipid-droplet-high microglia induced Tau phosphorylation and caspase activation in cultured neurons, supporting an effect on neurons. Our copy does not report an effect on brain memory; the neuronal effects were also observed with APOE3/3 microglia, so they are not shown to be unique to APOE4. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PI3K-AKT signaling is a key regulator of lipid metabolism, and PI3K inhibitors block the accumulation of LDs in numerous studies and study models.

    “PI3K-AKT signaling is another key regulator of lipid metabolism, and PI3K inhibitors have been shown to efficiently block the accumulation of LDs in numerous studies and in several study models [9, 64, 65].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [9]

    In “ACSL1 and triglycerides increase after fAβ challenge” (page unavailable), the paper reports that PI3K inhibitor GNE-317 dramatically reduced lipid-droplet formation in APOE4/4 human microglia exposed to fibrillar Aβ; it also describes PI3K inhibition as a known modulator of lipid droplets in mouse macrophages. These passages support a role for PI3K in lipid metabolism and an inhibitor effect in this model, but do not establish the broader claim that PI3K inhibitors efficiently block accumulation across numerous studies and several models, or specifically establish AKT’s role. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • APOE4 expression in human iMG induces secretion of lipids, which promotes tau phosphorylation in neurons.

    “APOE4 expression in human iMG was shown to induce secretion of lipids, which promoted tau phosphorylation in neurons63.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [63]

    The ‘LD+ iMG induce pTau and apoptosis in neurons’ section reports that conditioned media from lipid-high APOE4/4 human iMG induced neuronal Tau phosphorylation. But APOE3/3 iMG media had a similar effect, and the Discussion describes lipid transfer from microglia to neurons as a hypothesis, not an established cause of the phosphorylation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Both studies identified homeostatic, proliferative and lipid-associated types, and one other subtype with no functional data or tissue localization information.

    “Also, both studies identified homeostatic, proliferative and lipid-associated types60 (micro-PVM_4 in SEA-AD and Mic.6 and Mic.15 in ref. 13), and one other subtype with no functional data or tissue localization information.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [60]

    The ‘Lipid-associated ACSL1+ microglia in AD’ section (Fig. 1g–k; page unavailable) identifies homeostatic and lipid-associated microglial states. The passages do not identify a proliferative type or establish the claimed additional subtype without functional or tissue-localization information. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • BODIPY 493/503 detects lipid droplets consisting of neutral lipids.

    “BODIPY 493/503, a dye that detects LDs consisting of neutral lipids34,36”

    From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [36]

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.

  • ATAC-seq sequencing is labelled both single-end and paired-end

    Minor

    The method says the libraries were sequenced single-end, while "PE100" denotes paired-end 100-base sequencing.

  • Glucose tracer is described as deuterated but specified as 13C-labelled

    Minor

    The text calls the glucose tracer deuterated, but the specified U-13C6 glucose is labelled with carbon-13, not deuterium.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Palovics, R., Wyss-Coray, T. & Mirzasoleiman, B. Purification of single-cell transcriptomics data with coreset selection. In The 2022 ICML Workshop on Computational Biology Paper 67 (ICML, 2022).

Cited by

Sorted by citations

Related

Authors
Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C. M., Tsai, A., Guldner, I. H., Lamichhane, B. S., Smith, A., Schaum, N., Calcuttawala, K., Shin, A., Wang, Y.-H., Wang, C., Koutsodendris, N., Serrano, G. E., Beach, T. G., Reiman, E. M., Glass, C. K., Abu-Remaileh, M., Enejder, A., Huang, Y., & Wyss-Coray, T.
Affiliations
  • Stanford Medicine (US)
  • Gladstone Institutes (US)
  • Stanford University (US)
  • University of California San Diego (US)
  • Banner Sun Health Research Institute (US)
  • Banner Alzheimer’s Institute
  • University of California, San Francisco (US)
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-03-13
Volume
628
Issue
8006
Pages
154-161
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-07185-7
PMC
PMC10990924
OpenAlex
W4392762752
Semantic Scholar
403a5aefdc0c66f64029809243f84878c8677bae
Cited by
536
References
61
Citations by year
2026: 204 · 2025: 236 · 2024: 94 · 2023: 2
FWCI
125.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Pew Charitable Trusts
  • Alzheimer's Association
  • Alexander and Margaret Stewart Trust
  • Arizona Department of Health Services (P30 AG19610, U24 NS072026, 05-901, 211002)
  • Arizona Biomedical Research Commission (P30 AG19610, 05–901, U24 NS072026, 211002)
  • National Institute on Aging (RF1AG064928, P30AG019610, R03AG071791, P30AG062429, P30AG059307, P30AG072980, P30AG066515, R01AG069453, P01AG073082, T32AG000266)
  • National Institute of Neurological Disorders and Stroke (U24NS072026)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
Alzheimer's disease, APOE ε4, microglia, lipid droplets, ACSL1, lipid metabolism, amyloid-beta, triglyceride synthesis, tau phosphorylation, neurotoxicity, single-nucleus RNA sequencing, induced pluripotent stem cell-derived microglia, genetic risk factors
MeSH terms
Alzheimer Disease, Animals, Coenzyme A Ligases, Female, Humans, Male, Phosphorylation, Triglycerides, Amyloid beta-Peptides, tau Proteins, Culture Media, Conditioned, Microglia, Genetic Predisposition to Disease, Mice, Apolipoprotein E4, Induced Pluripotent Stem Cells, Lipid Droplets

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-16.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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