CoChat
Sign Up
Cited by 9Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems

Open access
Tian, Chunhui, Ao, Zheng, Cerneckis, Jonas, Cai, Hongwei, Chen, Lei, Niu, Hengyao, Takayama, Kazuo, Kim, Jungsu +4 more·2025·Science Advances
DOI 10.1126/sciadv.adu2708PMC PMC12372852
Open this paper in CoChat — free accountOpen PDF

Abstract

Increasing evidence strongly links neuroinflammation to Alzheimer’s disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in IL1B and CCL3 expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes’ role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper introduces human cortical organoid microphysiological systems (hCO-MPSs) made from doughnut-shape cortical organoids on 3D-printed devices in 96-well plates to model monocyte-driven Alzheimer’s disease neuroinflammation. It reports that AD patient monocytes show increased infiltration, reduced Aβ clearance, stronger inflammatory responses, and induce astrocyte activation and neuronal apoptosis, with IL-1β and CCL3 as key mediators.

Key findings

  • Engineered doughnut-shape hCOs had an average ring width of 0.5 mm, whereas conventional spherical hCOs had an average radius of 0.9 mm; the hCO-MPSs showed reduced necrosis, minimized hypoxia, and improved viability.
  • AD monocytes infiltrated hCO-MPSs significantly more than age-matched control monocytes, and Aβ treatment substantially increased AD monocyte—but not control monocyte—infiltration; nearly twice as many monocytes infiltrated hCO-MPSs compared with conventional spherical hCOs.
  • AD monocytes showed reduced Aβ phagocytosis and down-regulated phagocytosis/Aβ catabolism genes, while inflammatory genes such as S100A8 and LYZ were among the most up-regulated; AD monocyte coculture increased astrocyte activation, ROS production, and neuronal apoptosis, further amplified by Aβ.
  • IL1B and CCL3 were the most up-regulated cytokine-encoding genes in AD monocyte–cocultured hCO-MPSs, with increased IL-1β and CCL3 protein by ELISA; neutralizing CCL3 reduced monocyte infiltration, and neutralizing IL-1β or CCL3 decreased astrocyte activation and neuronal apoptosis.

Methods

  • hCO-MPSs were generated by culturing WA09 hESC-derived cortical organoids on 3D-printed perfusable scaffolds in 96-well plates, forming doughnut-shape hCOs; monocytes were isolated from PBMCs of patients with AD and age-matched control donors, with THP-1 cells used in preliminary coculture experiments.
  • The study used time-lapse imaging, immunostaining, live/dead and hypoxia assays, TUNEL, ROS measurement, ELISA, qPCR, bulk RNA-seq, and single-cell RNA-seq of monocyte-enriched hCO-MPSs.
  • Analyses included DEG identification, GO enrichment, Seurat-based scRNA-seq clustering/annotation, and statistical comparisons using unpaired t tests in GraphPad Prism 8.

Limitations

  • The paper states that the model lacks a functional blood-brain barrier, lacks microglia, oligodendrocytes, T cells, and B cells, and does not incorporate AD-related genotypes, limiting its ability to explore deeper pathology.
  • The paper states that causal relationships between monocytes, IL-1β, CCL3, and AD neuroinflammation remain undetermined due to current model limitations.
  • Evident from the text: findings rely on an in vitro organoid-MPS coculture system with relatively small experimental groups, such as n = 5 organoids from three independent experiments for many quantifications.

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

Integrity signals

Registry

Crossref · 10.1126/sciadv.adu2708

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

30 of 42 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Neuroinflammation functions as a vital factor in AD pathogenesis.

    “Increasing clinical evidence suggests that neuroinflammation functions as a vital factor in AD pathogenesis (2)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] M. T. Heneka, M. J. Carson, J. el Khoury, G. E. Landreth, F. Brosseron, D. L. Feinstein, A. H. Jacobs, T. Wyss-Coray, J. Vitorica, R. M. Ransohoff, K. Herrup, S. A. Frautschy, B. Finsen, G. C. Brown, A. Verkhratsky, K. Yamanaka, J. Koistinaho, E. Latz, A. Halle, G. C. Petzold, T. Town, D. Morgan, M. L. Shinohara, V. H. Perry, C. Holmes, N. G. Bazan, D. J. Brooks, S. Hunot, B. Joseph, N. Deigendesch, O. Garaschuk, E. Boddeke, C. A. Dinarello, J. C. Breitner, G. M. Cole, D. T. Golenbock, M. P. Kummer, Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388– 405 (2015). 25792098 PMC59097 source
  • Interpretationcitation

    The significant up-regulation of S100A8 and LYZ suggests an enhanced inflammatory response in AD monocytes.

    “Given their major roles in the immune response and inflammation (54, 55), the significant up-regulation of S100A8 and LYZ suggested an enhanced inflammatory response in AD monocytes.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [54] J. Roth, M. Goebeler, C. Sorg, S100A8 and S100A9 in inflammatory diseases. Lancet 357, 1041 (2001). 11293617 source
    • cites [55] A. Bergamo, M. Gerdol, A. Pallavicini, S. Greco, I. Schepens, R. Hamelin, F. Armand, P. J. Dyson, G. Sava, Lysozyme-induced transcriptional regulation of TNF-α pathway genes in cells of the monocyte lineage. Int. J. Mol. Sci. 20, 5502 (2019). 31694163 PMC6862675 source
  • Findingown data

    AD monocytes colocalize with Aβ in hCO-MPSs.

    “AD monocytes also colocalized with Aβ in the hCO-MPSs (Fig. 2C), supporting the previous observations that infiltrated monocytes accumulate around Aβ plaques in the brain tissues of patients with AD (13).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] C. Muñoz-Castro, M. Mejias-Ortega, E. Sanchez-Mejias, V. Navarro, L. Trujillo-Estrada, S. Jimenez, J. A. Garcia-Leon, J. J. Fernandez-Valenzuela, M. V. Sanchez-Mico, C. Romero-Molina, I. Moreno-Gonzalez, D. Baglietto-Vargas, M. Vizuete, A. Gutierrez, J. Vitorica, Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus. Acta Neuropathol. Commun. 11, 31 (2023). 36855152 PMC9976401 source
  • Premisecitation

    The population of infiltrated monocytes increases as AD progression worsens.

    “The population of infiltrated monocytes was also found to increase as the AD progression worsens (13).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] C. Muñoz-Castro, M. Mejias-Ortega, E. Sanchez-Mejias, V. Navarro, L. Trujillo-Estrada, S. Jimenez, J. A. Garcia-Leon, J. J. Fernandez-Valenzuela, M. V. Sanchez-Mico, C. Romero-Molina, I. Moreno-Gonzalez, D. Baglietto-Vargas, M. Vizuete, A. Gutierrez, J. Vitorica, Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus. Acta Neuropathol. Commun. 11, 31 (2023). 36855152 PMC9976401 source
  • Premisecitation

    Human brain organoids can replicate the complex brain microenvironment better than 2D in vitro models.

    “With their 3D structures and cell components resembling the human brain, these organoids can replicate the complex brain microenvironment better than 2D in vitro models (15–17, 19)”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [15] M. A. Lancaster, M. Renner, C. A. Martin, D. Wenzel, L. S. Bicknell, M. E. Hurles, T. Homfray, J. M. Penninger, A. P. Jackson, J. A. Knoblich, Cerebral organoids model human brain development and microcephaly. Nature 501, 373– 379 (2013). 23995685 PMC3817409 source

      The Introduction describes 3D organoids with interacting brain-region identities and organization resembling the developing human brain; the Results report complex, heterogeneous tissues. These passages support the claim that organoids reproduce aspects of brain structure, but they do not establish that organoids replicate the brain microenvironment better than 2D in vitro models. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [16] A. M. Paşca, S. A. Sloan, L. E. Clarke, Y. Tian, C. D. Makinson, N. Huber, C. H. Kim, J.-Y. Park, N. A. O’Rourke, K. D. Nguyen, S. J. Smith, J. R. Huguenard, D. H. Geschwind, B. A. Barres, S. P. Paşca, Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671– 678 (2015). 26005811 PMC4489980 source
    • cites [17] C. A. Trujillo, R. Gao, P. D. Negraes, J. Gu, J. Buchanan, S. Preissl, A. Wang, W. Wu, G. G. Haddad, I. A. Chaim, A. Domissy, M. Vandenberghe, A. Devor, G. W. Yeo, B. Voytek, A. R. Muotri, Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558– 569.e7 (2019). 31474560 PMC6778040 source

      The Introduction describes organoids as three-dimensional models that mimic human brain development at the cellular and molecular levels, and the Results describe brain-like cell types and layered structures. Our copy does not establish that organoids replicate the brain microenvironment better than 2D in vitro models; searches for that comparison found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [19] F. Birey, J. Andersen, C. D. Makinson, S. Islam, W. Wei, N. Huber, H. C. Fan, K. R. C. Metzler, G. Panagiotakos, N. Thom, N. A. O’Rourke, L. M. Steinmetz, J. A. Bernstein, J. Hallmayer, J. R. Huguenard, S. P. Paşca, Assembly of functionally integrated human forebrain spheroids. Nature 545, 54– 59 (2017). 28445465 PMC5805137 source

      The Discussion (page unavailable) says the assembled 3D forebrain spheroids have advantages over adherent methods and capture developmental processes, including interneuron migration. The Assembly of Forebrain Spheroids section (page unavailable) reports that migration was inefficient or absent when spheroids were plated on a coverslip. These findings support an advantage for this specific 3D model, but not the broader claim that human brain organoids generally replicate the complex brain microenvironment better than 2D models. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 12
  • The quote only partly states this claim. 2

  • May combine two claims.

    Premisecitation

    Human brain organoids can fully replicate human biology and potentially reduce translational barriers from experimental findings to therapeutic applications.

    “Meanwhile, being entirely derived from human cells, these organoids can fully replicate human biology and potentially reduce the translational barriers from experimental findings to therapeutic applications (20–22), offering advantages over animal models (23–25).”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [20] J. Kim, B.-K. Koo, J. A. Knoblich, Human organoids: Model systems for human biology and medicine. Nat. Rev. Mol. Cell Biol. 21, 571– 584 (2020). 32636524 PMC7339799 source

      The ‘Bridging the gap between animal models and humans’ section says human organoids may represent human tissue more accurately than animal models, and the Conclusions describe their potential in clinical translational research. But ‘Assessing interactions with other organs and the environment’ says organoids mimic only part of the human body, so the claim that brain organoids can fully replicate human biology overstates the source. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [21] F. Liu, J. Huang, L. Zhang, J. Chen, Y. Zeng, Y. Tang, Z. Liu, Advances in cerebral organoid systems and their application in disease modeling. Neuroscience 399, 28– 38 (2019). 30578974 source
    • cites [22] G. Quadrato, J. Brown, P. Arlotta, The promises and challenges of human brain organoids as models of neuropsychiatric disease. Nat. Med. 22, 1220– 1228 (2016). 27783065 source
    • cites [23] D. Puzzo, W. Gulisano, A. Palmeri, O. Arancio, Rodent models for Alzheimer’s disease drug discovery. Expert Opin. Drug Discovery 10, 703– 711 (2015). PMC4592281 25927677 source

      The Expert opinion section (page unavailable) says animal models reproduce only some aspects of Alzheimer’s disease and cannot recapitulate the entire human clinical picture. That supports the comparison with animal models, but the paper does not address whether human brain organoids fully replicate human biology or reduce translational barriers. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [24] M. Jucker, The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat. Med. 16, 1210– 1214 (2010). 21052075 source
    • cites [25] H. Cai, Z. Ao, L. Hu, Y. Moon, Z. Wu, H. C. Lu, J. Kim, F. Guo, Acoustofluidic assembly of 3D neurospheroids to model Alzheimer’s disease. Analyst 145, 6243– 6253 (2020). 32840509 PMC7530134 source

      The Abstract says this paper’s neurospheroids were assembled from embryonic mouse brain cells, not entirely from human cells. The Conclusions describe an in vivo-like brain microenvironment and a potential bridge between cell cultures and in vivo studies, supporting the proposed research utility, but not the assertion that these organoids fully replicate human biology. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Aβ catabolism genes RAB5A, RAB11A, CLU, and LRP2 are down-regulated in AD monocytes, suggesting impaired Aβ catabolism in AD monocytes.

    “Similarly, several genes reported to be involved in Aβ catabolism, such as RAB5A, RAB11A, CLU, and LRP2 (49–53), were also down-regulated in AD monocytes, suggesting the impaired Aβ catabolism in AD monocytes.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [49] A. Zeigerer, J. Gilleron, R. L. Bogorad, G. Marsico, H. Nonaka, S. Seifert, H. Epstein-Barash, S. Kuchimanchi, C. G. Peng, V. M. Ruda, P. Del Conte-Zerial, J. G. Hengstler, Y. Kalaidzidis, V. Koteliansky, M. Zerial, Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature 485, 465– 470 (2012). 22622570 source
    • cites [50] E. Barbero-Camps, V. Roca-Agujetas, I. Bartolessis, C. de Dios, J. C. Fernández-Checa, M. Marí, A. Morales, T. Hartmann, A. Colell, Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion. Autophagy 14, 1129– 1154 (2018). 29862881 PMC6103708 source

      The citation is attached to the description of RAB5A, RAB11A, CLU, and LRP2 as genes involved in Aβ catabolism; the down-regulation in AD monocytes is the citing authors’ own finding. The Discussion mentions RAB5A only as an indicator of early endosomal enlargement, while the Introduction describes Aβ clearance without linking it to those four genes. Searches for the gene names and their roles in Aβ degradation found no passage establishing the cited claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [51] Z. Zhao, A. P. Sagare, Q. Ma, M. R. Halliday, P. Kong, K. Kisler, E. A. Winkler, A. Ramanathan, T. Kanekiyo, G. Bu, N. C. Owens, S. V. Rege, G. Si, A. Ahuja, D. Zhu, C. A. Miller, J. A. Schneider, M. Maeda, T. Maeda, T. Sugawara, J. K. Ichida, B. V. Zlokovic, Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18, 978– 987 (2015). 26005850 PMC4482781 source

      The Results section on Aβ endothelial transcytosis links Rab5 and Rab11 to Aβ trafficking and clearance, supporting their involvement in Aβ handling. It describes transport away from degradation, however, and reports that Rab11b—not Rab11a—was required in brain endothelium; it does not establish CLU or LRP2 involvement in Aβ catabolism. The reported down-regulation in AD monocytes is the citing authors’ observation, not a finding attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [52] E. M. Foster, A. Dangla-Valls, S. Lovestone, E. M. Ribe, N. J. Buckley, Clusterin in Alzheimer’s disease: Mechanisms, genetics, and lessons from other pathologies. Front. Neurosci. 13, 164 (2019). 30872998 PMC6403191 source

      The review’s “Clusterin and Aβ Metabolism” section (page unavailable) links CLU and LRP2 to Aβ uptake, transport, and clearance. It does not establish the claimed roles of RAB5A or RAB11A. The down-regulation in AD monocytes appears to be the citing authors’ own finding, rather than a finding attributed to this review. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [53] B. V. Zlokovic, S. Yamada, D. Holtzman, J. Ghiso, B. Frangione, Clearance of amyloid β-peptide from brain: Transport or metabolism? Nat. Med. 6, 718 (2000). 10888893 source
    • Rests on an assumption: Gene expression changes in monocytes, astrocytes, and neurons within hCO-MPSs reflect functional capacities in the human AD brain.

  • May combine two claims.

    Premisecitation

    Postmortem AD brain tissues show extensive monocyte infiltration into the brain parenchyma, where monocytes cluster around amyloid-β plaques.

    “End point analyses of postmortem AD brain tissues show extensive monocyte infiltration into the brain parenchyma of patients with AD, where they cluster around amyloid-β (Aβ) plaques (13, 14).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] C. Muñoz-Castro, M. Mejias-Ortega, E. Sanchez-Mejias, V. Navarro, L. Trujillo-Estrada, S. Jimenez, J. A. Garcia-Leon, J. J. Fernandez-Valenzuela, M. V. Sanchez-Mico, C. Romero-Molina, I. Moreno-Gonzalez, D. Baglietto-Vargas, M. Vizuete, A. Gutierrez, J. Vitorica, Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus. Acta Neuropathol. Commun. 11, 31 (2023). 36855152 PMC9976401 source

      The Discussion (page not provided) reports monocyte infiltration into AD hippocampal parenchyma and an association of CD163-positive cells with amyloid-β plaques. It does not support describing infiltration as extensive across AD brains: the authors call the population small, report substantial variation between patients, and note that some AD cases had little or no infiltration. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [14] C. Fernández Zapata, G. Giacomello, E. J. Spruth, J. Middeldorp, G. Gallaccio, A. Dehlinger, C. Dames, J. K. H. Leman, R. E. van Dijk, A. Meisel, S. Schlickeiser, D. Kunkel, E. M. Hol, F. Paul, M. K. Parr, J. Priller, C. Böttcher, Differential compartmentalization of myeloid cell phenotypes and responses towards the CNS in Alzheimer’s disease. Nat. Commun. 13, 7210 (2022). 36418303 PMC9684147 source

      The Results section on the choroid plexus and brain parenchyma reports infiltrating macrophages in postmortem AD grey frontal matter, but it does not establish extensive monocyte infiltration: it found no difference in cell-cluster abundance between AD and controls. The passages do not report monocytes clustering around Aβ plaques. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Phagocytosis-related genes FCER1G, FCGR2A, TYROBP, and GAS6 are down-regulated in AD monocytes compared with AC monocytes, indicating a reduced ability of AD monocytes to phagocytose Aβ.

    “We found that the expression of phagocytosis-related genes, including FCER1G, FCGR2A, TYROBP, and GAS6 (46–48), was down-regulated in AD monocytes as compared to AC monocytes (Fig. 3C), indicating a reduced ability of AD monocytes to phagocytose Aβ.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [46] S. Bournazos, T. T. Wang, J. V. Ravetch, The role and function of Fcγ receptors on myeloid cells. Microbiol. Spectr. 4, 10.1128/microbiolspec.MCHD-0045-2016 (2016). PMC5240797 28087938 source

      The sections on FcγR types and on Phagocytosis and Antigen Presentation (page unavailable) identify FCER1G as encoding an Fc-receptor signaling chain, FCGR2A as encoding FcγRIIa, and Fcγ receptors as mediators of phagocytosis. The citation is attached to the description of the genes as phagocytosis-related, not to the citing authors’ own finding of down-regulation. Our copy does not establish that TYROBP or GAS6 are phagocytosis-related, so it supports only part of the cited gene list. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [47] S. Shangguan, P. K. Ehrenberg, A. Geretz, L. Yum, G. Kundu, K. May, S. Fourati, K. Nganou-Makamdop, L. D. Williams, S. Sawant, E. Lewitus, P. Pitisuttithum, S. Nitayaphan, S. Chariyalertsak, S. Rerks-Ngarm, M. Rolland, D. C. Douek, P. Gilbert, G. D. Tomaras, N. L. Michael, S. Vasan, R. Thomas, Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1. eLife 10, e69577 (2021). 34533134 PMC8514236 source

      The Results section (page unavailable) identifies TYROBP as a phagocytosis-pathway gene, and the Discussion describes its role in promoting phagocytosis. Our copy does not establish FCER1G, FCGR2A, or GAS6 as phagocytosis-related genes. The AD-versus-AC expression finding is presented as the citing authors’ own result, not as a finding attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [48] C. Grommes, C. Y. Lee, B. L. Wilkinson, Q. Jiang, J. L. Koenigsknecht-Talboo, B. Varnum, G. E. Landreth, Regulation of microglial phagocytosis and inflammatory gene expression by Gas6 acting on the Axl/Mer family of tyrosine kinases. J. Neuroimmune Pharmacol. 3, 130– 140 (2008). 18247125 PMC3653274 source
    • Rests on an assumption: Gene expression changes in monocytes, astrocytes, and neurons within hCO-MPSs reflect functional capacities in the human AD brain.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The cells projected on the UMAP space were annotated using canonical marker genes for neurons, progenitors, intermediate progenitors, astrocytes, other glial cells, and monocytes.

    “The cells projected on the UMAP space were annotated using canonical marker genes for neurons, progenitors, intermediate progenitors, astrocytes, other glial cells, and monocytes (17, 84, 85).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [17] C. A. Trujillo, R. Gao, P. D. Negraes, J. Gu, J. Buchanan, S. Preissl, A. Wang, W. Wu, G. G. Haddad, I. A. Chaim, A. Domissy, M. Vandenberghe, A. Devor, G. W. Yeo, B. Voytek, A. R. Muotri, Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558– 569.e7 (2019). 31474560 PMC6778040 source

      The Results section (‘Generation of functional cortical organoids’; page unavailable) says cells were classified using gene markers into progenitors, intermediate progenitors, glial cells, and two neuronal classes. STAR METHODS (‘Methods Details’; page unavailable) describes plotting the clusters on UMAP. The copy does not report monocytes or astrocytes as separate annotated classes, so it does not support the full list in the claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [84] M. Y. Batiuk, A. Martirosyan, J. Wahis, F. de Vin, C. Marneffe, C. Kusserow, J. Koeppen, J. F. Viana, J. F. Oliveira, T. Voet, C. P. Ponting, T. G. Belgard, M. G. Holt, Identification of region-specific astrocyte subtypes at single cell resolution. Nat. Commun. 11, 1220 (2020). 32139688 PMC7058027 source

      The Results section (‘Single-cell mRNA sequencing reveals astrocyte heterogeneity’; page unavailable) says cell types were identified using known marker genes, supporting the annotation method. But this paper shows tSNE plots, not UMAP, and the passages do not establish the full listed set of cell types, particularly monocytes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [85] J. Andersen, N. Thom, J. L. Shadrach, X. Chen, M. M. Onesto, N. D. Amin, S. J. Yoon, L. Li, W. J. Greenleaf, F. Müller, A. M. Pașca, J. A. Kaltschmidt, S. P. Pașca, Single-cell transcriptomic landscape of the developing human spinal cord. Nat. Neurosci. 26, 902– 914 (2023). 37095394 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The CCL3/CCR1 axis is known to mediate monocyte recruitment during inflammation.

    “The CCL3/CCR1 axis is known to mediate monocyte recruitment during inflammation (66), underscoring its potential role in attracting more monocytes into the brain in AD and thus further exacerbating neuroinflammation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [66] X. Zhao, M. Gu, X. Xu, X. Wen, G. Yang, L. Li, P. Sheng, F. Meng, CCL3/CCR1 mediates CD14+CD16− circulating monocyte recruitment in knee osteoarthritis progression. Osteoarthr. Cartil. 28, 613– 625 (2020). 32006659 source

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

    Premisecitation

    Guided cortical organoid differentiation yields highly reproducible organoids compared with unguided organoid differentiation.

    “Furthermore, several studies have shown that guided cortical organoid differentiation yields highly reproducible organoids as compared to unguided organoid differentiation (72–74).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [72] D. Rosebrock, S. Arora, N. Mutukula, R. Volkman, E. Gralinska, A. Balaskas, A. A. Hernández, R. Buschow, B. Brändl, F.-J. Müller, P. F. Arndt, M. Vingron, Y. Elkabetz, Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells. Nat. Cell Biol. 24, 981– 995 (2022). 35697781 PMC9203281 source
    • cites [73] S. J. Yoon, L. S. Elahi, A. M. Pașca, R. M. Marton, A. Gordon, O. Revah, Y. Miura, E. M. Walczak, G. M. Holdgate, H. C. Fan, J. R. Huguenard, D. H. Geschwind, S. P. Pașca, Reliability of human cortical organoid generation. Nat. Methods 16, 75– 78 (2019). 30573846 PMC6677388 source
    • cites [74] S. Velasco, A. J. Kedaigle, S. K. Simmons, A. Nash, M. Rocha, G. Quadrato, B. Paulsen, L. Nguyen, X. Adiconis, A. Regev, J. Z. Levin, P. Arlotta, Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570, 523– 527 (2019). 31168097 PMC6906116 source

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

    Premisecitation

    IL-1β is a pro-inflammatory cytokine and key mediator of neuronal injury.

    “Meanwhile, IL-1β, a pro-inflammatory cytokine and key mediator of neuronal injury (67), may further activate astrocytes and contribute to neuronal degeneration.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [67] F. Buffolo, V. Petrosino, M. Albini, M. Moschetta, F. Carlini, T. Floss, N. K. de Rosbo, F. Cesca, A. Rocchi, A. Uccelli, F. Benfenati, Neuroinflammation induces synaptic scaling through IL-1β-mediated activation of the transcriptional repressor REST/NRSF. Cell Death Dis. 12, 180 (2021). 33589593 PMC7884694 source

  • The quote only partly states this claim.

    Findingown data

    hCO-MPSs have improved cell viability compared with conventional hCOs.

    “By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The hCO-MPS model recapitulates key aspects of the human AD brain microenvironment sufficiently to study monocyte-mediated neuroinflammation.

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    hCO-MPSs with doughnut-shape hCOs have reduced necrosis and minimized hypoxia compared with conventional spherical hCOs.

    “By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The hCO-MPS model recapitulates key aspects of the human AD brain microenvironment sufficiently to study monocyte-mediated neuroinflammation.

  • May combine two claims.

    Findingown data

    The doughnut-like shape, shaking flow, and perfusable scaffold promote efficient nutrient and oxygen exchange, leading to significantly increased hCO cell viability on-device culture.

    “Furthermore, the doughnut-like shape as well as the shaking flow and the perfusable scaffold promote efficient nutrient and oxygen exchange, leading to significantly increased hCO cell viability on-device culture (Fig. 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AC monocytes show extensive colocalization of Aβ and monocyte signals, whereas the overlap is reduced in AD monocytes.

    “Upon closer inspection of monocyte-infiltrated hCO-MPSs, we detected an extensive colocalization of Aβ (green) and monocyte (red) signals in AC monocytes, whereas the overlap was reduced in AD monocytes (Fig. 3, A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Doughnut-shape hCOs contain mature MAP2-positive neurons and GFAP-positive astrocytes and exhibit ventricular zone-like tissue organization.

    “Doughnut-shape hCOs contain mature microtubule-associated protein 2–positive (MAP2+) neurons and glial fibrillary acidic protein–positive (GFAP+) astrocytes as well as exhibit ventricular zone (VZ)–like tissue organization (Fig. 1E and fig. S3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spherical hCOs have an average radius of 0.9 mm and cannot be efficiently supplied with oxygen and nutrients due to diffusion constraints, resulting in an obvious hypoxic core.

    “In contrast, a substantial portion of spherical hCOs that has an average radius of 0.9 mm (fig. S3, B and C) cannot be efficiently supplied with oxygen and nutrients due to diffusion constraints, resulting in the formation of an obvious hypoxic core (Fig. 1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ treatment substantially increases infiltration of AD monocytes, but not AC monocytes, into hCO-MPSs.

    “Furthermore, Aβ treatment mimicking AD brain environment substantially increased the infiltration of AD monocytes, but not AC monocytes, into hCO-MPSs, underscoring the role of Aβ in peripheral monocyte infiltration in patients with AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Aβ treatment mimics the AD brain environment.

  • May combine two claims.

    Findingown data

    GO enrichment analysis based on DEGs revealed up-regulation of pathways associated with neuronal development and down-regulation of pathways related to cell cycle regulation, apoptosis, and stress response in engineered doughnut-shape hCOs.

    “Gene ontology (GO) enrichment analysis based on DEGs revealed up-regulation of pathways associated with multiple aspects of neuronal development and down-regulation of pathways related to cell cycle regulation, apoptosis, and stress response (fig. S4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GO enrichment analysis confirms pathways related to elevated inflammatory response and cell migration, as well as reduced phagocytosis and Aβ metabolism in AD monocytes.

    “Consistent with our in vitro findings, GO enrichment analysis confirmed pathways related to elevated inflammatory response and cell migration, as well as reduced phagocytosis and Aβ metabolism in AD monocytes (Fig. 3E and fig. S6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    hCO-MPSs with engineered doughnut-shape hCOs have an average ring width of 0.5 mm, effectively preventing hypoxia and necrosis in organoids.

    “Specifically, hCO-MPSs with the engineered doughnut-shape hCOs have an average ring width of 0.5 mm (fig. S3, B and C), effectively preventing hypoxia and necrosis in organoids (Fig. 1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TUNEL analysis reveals significantly higher neuronal apoptosis in AD monocyte-cocultured hCO-MPSs compared with AC monocyte cocultures, further increased in the presence of Aβ.

    “TUNEL analysis revealed significantly higher neuronal apoptosis in AD monocyte-cocultured hCO-MPSs as compared to AC monocyte cocultures, which was further increased in the presence of Aβ (Fig. 5C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Aβ treatment mimics the AD brain environment.

  • May combine two claims.

    Findingown data

    GO analysis reveals enrichment among up-regulated DEGs for apoptosis, DNA damage, and stress response processes, and among down-regulated DEGs for synapse organization, neuron development, and neuron projection extension processes.

    “Last, GO analysis revealed enrichment among up-regulated DEGs for apoptosis, DNA damage, and stress response processes, as well as enrichment among down-regulated DEGs for synapse organization, neuron development, and neuron projection extension processes (Fig. 5E and fig. S6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    scRNA-seq data reveal that IL1B and CCL3 are expressed in astrocytes and monocytes in AD monocyte-cocultured hCO-MPSs, suggesting that both cell types may contribute to the production of IL-1β and CCL3 proteins, with monocytes being the predominant source.

    “The scRNA-seq data revealed that IL1B and CCL3 are expressed in astrocytes and monocytes in AD monocyte-cocultured hCO-MPSs, suggesting that both cell types may contribute to the production of IL-1β and CCL3 proteins, with monocytes being the predominant source (fig. S10).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IL1B and CCL3 expression in hCO-MPSs reflects cytokine levels in the AD brain.

  • May combine two claims.

    Interpretationreasoning

    hCO-MPSs are simple, robust, and scalable due to the employment of simple 3D printing technology.

    “our MPSs are simple, robust, and scalable, due to the employment of simple 3D printing technology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AD monocytes in hCO-MPSs have altered functionality, including impaired Aβ clearance ability and increased inflammatory response.

    “Overall, we found the altered functionality of AD monocytes in hCO-MPSs, including impaired Aβ clearance ability and increased inflammatory response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The engineered MPS supports efficient hCO differentiation and maturation, resolves hypoxia, and can be easily scaled for high-throughput experiments.

    “Thus, we engineered a MPS that supports efficient hCO differentiation and maturation, resolves hypoxia, and can be easily scaled for high-throughput experiments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Down-regulated SOX2 and Tuj1, reduced cell cycle-related genes, and up-regulated MAP2 and GFAP suggest enhanced cellular maturation in engineered doughnut-shape hCOs.

    “Specifically, the down-regulated gene expression of SOX2 and Tuj1 (TUBB3) (early development), as well as reduced cell cycle–related genes and pathways, along with the up-regulated gene expression of MAP2 and GFAP (mature neuron and astrocytes), suggested enhanced cellular maturation in the engineered doughnut-shape hCOs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Monocytes can readily clear Aβ deposits, but their clearing capacity is decreased in AD.

    “These findings indicate that although monocytes can readily clear Aβ deposits, their clearing capacity is decreased in AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Functional in vitro experiments and gene expression changes reveal distinct increased infiltration of AD monocytes into brain-like tissue, further enhanced by Aβ.

    “In summary, the functional in vitro experiments and gene expression changes both revealed the distinct increased infiltration of AD monocytes into the brain-like tissue, which further enhanced in the presence of Aβ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Doughnut-shape hCOs enhance oxygen and nutrient diffusion to eliminate necrotic and hypoxic conditions and facilitate incorporation of immunocytes compared with conventional spheroidal hCOs.

    “They can not only enhance oxygen/nutrient diffusion to eliminate the necrotic and hypoxic conditions but also facilitate the incorporation of immunocytes (e.g., monocytes), compared to conventional spheroidal hCOs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The hCO-MPS model recapitulates key aspects of the human AD brain microenvironment sufficiently to study monocyte-mediated neuroinflammation.

  • May combine two claims.

    Interpretationown data

    Higher expression of CTIP2 and TBR1 supports improved development and greater cortical specificity in engineered doughnut-shape organoids.

    “Meanwhile, the higher expression of CTIP2 (BCL11B) and TBR1, canonical markers of the cortical plate, further supports improved development and greater cortical specificity in the engineered doughnut-shape organoids (fig. S4C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    hCO-MPSs are compatible with time-lapse imaging, enabling the study of monocyte infiltration dynamics.

    “Furthermore, hCO-MPSs are compatible with time-lapse imaging, enabling the study of monocyte infiltration dynamics, whereas the 3D-printed scaffold device is easy to generate, user-friendly, and compatible with commonly used organoid differentiation protocols.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Monocytes derived from patients with AD may contain cell-intrinsic properties specific to that patient.

    “The use of primary human monocytes also has several advantages: (i) their human origin enables the study of human-specific disease phenotypes and molecular mechanisms, (ii) monocytes derived from patients with AD may contain cell-intrinsic properties specific to that patient, and (iii) monocytes derived from patients with AD and age-matched controls may exhibit age-relevant phenotypes, given that”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The 3D-printed scaffold device is easy to generate, user-friendly, and compatible with commonly used organoid differentiation protocols.

    “Furthermore, hCO-MPSs are compatible with time-lapse imaging, enabling the study of monocyte infiltration dynamics, whereas the 3D-printed scaffold device is easy to generate, user-friendly, and compatible with commonly used organoid differentiation protocols.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Cells with nFeature_RNA between 200 and 7000, nCount_RNA less than 25,000, and percent.mt less than 10% were kept in the dataset for downstream analysis.

    “cells with nFeature_RNA between 200 and 7000, nCount_RNA less than 25,000, and percent.mt less than 10% were kept in the dataset for downstream analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    AD monocytes can induce neuronal apoptosis and may contribute to neurodegeneration in AD.

    “Together, these findings indicate that AD monocytes can induce neuronal apoptosis and thus may contribute to neurodegeneration in AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AD monocytes exhibit enhanced infiltration, reduced Aβ clearance, and stronger inflammatory responses, and induce astrocyte activation and neuronal apoptosis, underscoring the exacerbating role of monocytes in AD neuroinflammation, with IL-1β and CCL3 as key mediators.

    “Using this model, we observed that AD monocytes exhibit enhanced infiltration, reduced Aβ clearance, and stronger inflammatory responses, as well as induce astrocyte activation and neuronal apoptosis, underscoring the exacerbating role of monocytes in AD neuroinflammation, with IL-1β and CCL3 as key mediators.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IL1B and CCL3 expression in hCO-MPSs reflects cytokine levels in the AD brain.

  • May combine two claims.

    Interpretationown data

    hCO-MPSs comprise doughnut-shape organoids on 3D-printed devices in 96-well plates, reduce necrosis and hypoxia, and facilitate immune cell infiltration.

    “These hCO-MPSs comprise doughnut-shape organoids on 3D-printed devices in 96-well plates, reduce necrosis and hypoxia, and facilitate immune cell infiltration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cortical neuropathology is evident in AD and contributes to cognitive decline.

    “We specifically chose to use cortical organoids because cortical neuropathology is evident in AD and contributes to cognitive decline (71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] R. van der Kant, L. S. B. Goldstein, R. Ossenkoppele, Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci. 21, 21– 35 (2020). 31780819 source

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

    Study design and conductnone given

    Genes expressed in less than 10 cells were excluded to remove low quality genes.

    “Genes expressed in less than 10 cells were excluded to remove low quality genes;”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Each qPCR reaction was performed in triplicate.

    “Each qPCR reaction was performed in triplicate.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Only DEGs with a P value of <0.05 were included in the analysis.

    “Only DEGs with a P value of <0.05 were included in the analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Only GO terms with a P value of <0.05 were included in the analysis.

    “Only GO terms with a P value of <0.05 were included in the analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The hCO-MPS model does not include a functional BBB, which is important for regulating monocyte entry.

    “Firstly, the model does not include a functional BBB, which is important for regulating monocyte entry.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The hCO-MPS model lacks essential cell components: microglia, oligodendrocytes, T cells, and B cells.

    “Secondly, the model lacks essential cell components: brain glial cells involved in neuroinflammation such as microglia and oligodendrocytes, as well as peripheral immune cells implicated in AD including T cells and B cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    AD-related genotypes are not incorporated in the hCO-MPS model, preventing exploration of deep pathology.

    “Furthermore, AD-related genotypes are not incorporated, preventing the model from exploring the deep pathology.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Gene expressions were normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase.

    “Gene expressions were normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The unique design of engineered scaffolds enhances oxygen and nutrient exchange across the organoid tissue, prevents hypoxia and necrosis of the organoid core, and supports peripheral monocyte infiltration and retention within the organoid.

    “The unique design of engineered scaffolds enhances oxygen and nutrient exchange across the organoid tissue, prevents hypoxia and necrosis of the organoid core, and supports peripheral monocyte infiltration and retention within the organoid.”
    Quote in the paperSubstantial claim
46 of 46

  • The paper relies on this without support.

    AD monocytes derived from PBMCs of patients with AD carry patient-specific disease information.

    “AD monocytes, derived from the peripheral blood mononuclear cells (PBMCs) of patients with AD, carry patient-specific disease information.”

  • The paper relies on this without support.

    The hCO-MPS model recapitulates key aspects of the human AD brain microenvironment sufficiently to study monocyte-mediated neuroinflammation.

    “When integrated with cortical organoids generated from human iPSCs, which provide a 3D human brain microenvironment, the MPS allows us to investigate monocyte-mediated AD neuroinflammation.”

  • The paper relies on this without support.

    Aβ treatment mimics the AD brain environment.

    “Furthermore, Aβ treatment mimicking AD brain environment substantially increased the infiltration of AD monocytes, but not AC monocytes, into hCO-MPSs”

  • The paper relies on this without support.

    LPS/IFN-γ prestimulated THP-1 cells simulate the activated state of AD monocytes and the AD brain environment.

    “the condition that simulated the activated state of AD monocytes and the AD brain environment (lipopolysaccharide/interferon-γ prestimulated THP-1 cells in Aβ-pretreated doughnut-shape hCOs)”

  • The paper relies on this without support.

    Monocytes from AD patients and age-matched controls are representative of peripheral monocytes relevant to AD neuroinflammation.

    “monocytes isolated from PBMCs of patients with AD and age-matched control (AC) donors (table S1)”

  • The paper relies on this without support.

    Gene expression changes in monocytes, astrocytes, and neurons within hCO-MPSs reflect functional capacities in the human AD brain.

    “Consistent with our in vitro findings, GO enrichment analysis confirmed pathways related to elevated inflammatory response and cell migration, as well as reduced phagocytosis and Aβ metabolism in AD monocytes”

  • The paper relies on this without support.

    IL1B and CCL3 expression in hCO-MPSs reflects cytokine levels in the AD brain.

    “The above findings demonstrate that IL-1β and CCL3 are key mediators in monocyte-driven neuroinflammation in AD”

  • The paper relies on this without support.

    Dynamic interactions of monocytes and brain parenchyma remain poorly understood in AD neuroinflammation, partly due to the absence of suitable human models.

    “However, dynamic interactions of monocytes and brain parenchyma remain poorly understood in AD neuroinflammation, partly due to the absence of suitable human models.”
8 of 8

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.

  • Organoid cell source is described as both iPSCs and hESCs

    Minor

    The Results describe the cortical organoids as generated from human iPSCs, but the organoid-generation method specifies WA09 human embryonic stem cells.

  • The same significance symbol is assigned two thresholds

    Minor

    The statistical-significance key assigns ** to both P < 0.01 and P < 0.005, so a result marked ** has no unambiguous threshold.

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Tian, C., Ao, Z., Cerneckis, J., Cai, H., Chen, L., Niu, H., Takayama, K., Kim, J., Shi, Y., Gu, M., Kanekiyo, T., & Guo, F.
Affiliations
  • Indiana University Bloomington (US)
  • City Of Hope National Medical Center (US)
  • Kyoto University (JP)
  • Indiana University Indianapolis (US)
  • University of California, Los Angeles (US)
  • Mayo Clinic (US)
Corresponding author
  • Tian, Chunhui
  • Ao, Zheng
  • Guo, Feng
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-08-22
Volume
11
Issue
34
Pages
eadu2708-eadu2708
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adu2708
PMC
PMC12372852
OpenAlex
W4413419019
Semantic Scholar
46936959ff3eafd3907ecf2736e4307d064835ec
Cited by
9
References
87
Citations by year
2026: 9
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc)
  • PubMed Central (submittedVersion, cc-by-nc)
Funders
  • National Institute on Aging (U54AG090792, R01 AG072291)
  • National Institute on Drug Abuse (U01DA056242)
  • National Institute of Allergy and Infectious Diseases (DP2AI160242)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, neuroinflammation, monocytes, microphysiological systems, 3D-printed device, amyloid-beta clearance, monocyte infiltration, astrocyte activation, neuronal apoptosis, IL-1β, CCL3, disease modeling
MeSH terms
Neuroinflammatory Diseases, Microphysiological Systems, Aged, Alzheimer Disease, Astrocytes, Cerebral Cortex, Female, Humans, Inflammation, Male, Monocytes, Neurons, Organoids, Amyloid beta-Peptides, Interleukin-1beta

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 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review