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Cited by 0Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses

Open access
Park, Jung Hyun, Kim, Byungwook, Al‐Amin, Md Mamun, Tate, Mason Douglas, Sharify, Ahmad Daniel, John, Sutha K., Karahan, Hande, Lu, Hui‐Chen +2 more·2026·Alzheimer's & Dementia
DOI 10.1002/alz.71742PMC PMC13457352
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Abstract

INTRODUCTION: Alzheimer's disease (AD) features amyloid beta (Aβ) plaques and tau tangles, yet how their coexistence reshapes brain transcriptomic programs remains unclear. METHODS: We performed high‐quality, sex‐balanced single‐nucleus RNA sequencing of 5XFAD (Aβ), PS19 (tau), and combined 5XFAD;PS19 mice. RESULTS: We identified transcriptional programs that emerged most prominently under combined pathology. These programs included disruption of glial lipid metabolism and immune pathways at the network level, alongside immune and synaptic alterations coordinated between microglia and oligodendrocytes. Cross‐species analyses further revealed that the pathway‐level alterations under combined pathology, particularly in immune, lipid, and cell cycle programs, exhibited the strongest concordance with human AD datasets, underscoring their translational relevance. DISCUSSION: Beyond benchmarking mouse models, this study provides a high‐quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network‐level systems pharmacology approach.

AI snapshot

Written from the paper’s full text.

TL;DR

In a sex-balanced snRNA-seq resource comparing 5XFAD, PS19, and 5XFAD;PS19 mouse cortex, combined Aβ/tau pathology produced transcriptomic programs not seen in single-pathology models, especially glial lipid dysregulation and coordinated microglial–oligodendrocyte immune/synaptic changes. The 5XFAD;PS19 model showed the strongest pathway-level concordance with human AD datasets.

Key findings

  • snRNA-seq retained 170,918 high-quality nuclei and 38 clusters; only 5XFAD;PS19 showed significant cell-type proportion shifts versus WT, with decreased excitatory neurons and astrocytes and increased oligodendrocytes and microglia; ExN_11 and O_3 were significantly changed.
  • hdWGCNA identified 13 co-expression modules; Mod2 lipid metabolism was downregulated broadly in 5XFAD;PS19 (all astrocyte clusters, OPC, endothelial cells, InN_3), Mod6 immune/microglial activation was upregulated, and neuronal Mod5/Mod7 synaptic modules were downregulated only in the combined model.
  • Differential expression found 2,922 DEGs across comparisons; 1,921 (66%) were exclusive to 5XFAD;PS19, enriched for immune response, lipid metabolism, and synaptic function; M_2 microglia and O_3 oligodendrocytes showed synapse-related gene suppression and shared Mod6 enrichment.
  • CellChat inferred increased interactions and signaling strength in 5XFAD;PS19, with microglial/oligodendrocyte-driven PROS and VISTA immune pathways; cross-species comparison with AMP-AD (>1200 individuals, 30 modules) showed 5XFAD;PS19 had concordant enrichment terms in 15 of 19 AD biodomains.

Methods

  • Crossbred 5XFAD and PS19 mice to generate WT, 5XFAD, PS19, and 5XFAD;PS19 littermates; used 9-month-old cortex, equal males/females, two mice per sex per genotype (n = 16); validated Aβ42 and p-tau-T231 by Meso Scale Discovery assay.
  • Machine-assisted nuclei isolation, 10x Chromium 3′ v3.1 snRNA-seq; Cell Ranger GRCm38, SoupX, DoubletFinder, Seurat/SCTransform, Harmony; retained 170,918 nuclei; clustering/annotation at resolution 0.6.
  • Analyses included hdWGCNA co-expression modules, MAST differential expression, speckle cell proportions, CellChat communication, pseudobulk DESeq2, and AMP-AD cross-species Pearson/GSEA with AD biodomains.

Limitations

  • Stated: parental transgenic lines overexpress familial AD/FTD mutations and do not fully recapitulate slow human amyloid/tau accumulation; more physiological knock-in models remain undercharacterized.
  • Stated: CellChat predictions are computational, based on expression and a curated ligand–receptor database, and require experimental validation; cross-species comparison is constrained by tissue context, disease staging, analytical framework, and postmortem interval effects.
  • Evident: the study is cortex-only at a single 9-month time point and does not report sex-specific analyses despite sex-balanced sampling, so regional, temporal, and sex-specific generalization is not established.

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

Integrity signals

Registry

Crossref · 10.1002/alz.71742

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

55 of 67 cited sources checked · 31 supported · 2 flagged · accuracy not yet measured

  • Findingown data

    hdWGCNA identified synaptic, immune, and lipid-metabolism modules that demonstrated the most pronounced alterations in the combined 5XFAD;PS19 model.

    “Using high‐dimensional weighted gene co‐expression network analysis (hdWGCNA), 23 we identified synaptic, immune, and lipid‐metabolism modules that demonstrated the most pronounced alterations in the combined 5XFAD;PS19 model.”
    • Also stated in: § RESULTS · plain
      “We identified transcriptional programs that emerged most prominently under combined pathology.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Morabito S, Reese F, Rahimzadeh N, Miyoshi E, Swarup V. hdWGCNA identifies co‐expression networks in high‐dimensional transcriptomics data. Cell Reports Methods. 2023; 3(6): 100498. doi: 10.1016/j.crmeth.2023.100498 37426759 PMC10326379 source
  • Premisecitation

    Most preclinical studies have examined Aβ and tau in isolation using either Aβ amyloidosis models or tauopathy models.

    “However, most preclinical studies have examined Aβ and tau in isolation, using either Aβ amyloidosis models that develop robust Aβ deposition without tau pathology, or tauopathy models that accumulate hyperphosphorylated tau in the absence of Aβ.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Granzotto A, Vissel B, Sensi SL. Lost in translation: inconvenient truths on the utility of mouse models in Alzheimer's disease research. eLife. 2024; 13: e90633. doi: 10.7554/eLife.90633 39329365 PMC11434637 source

      The Introduction’s Quantitative section says APP or tau-overexpressing mice remain the primary tools for AD research. Its Qualitative section describes the lack of tau pathology in APP models and hyperphosphorylated-tau inclusions in tau models. It does not establish the citing sentence’s further assertion that tauopathy models lack Aβ. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [10] Pádua MS, Guil‐Guerrero JL, Prates JAM, Lopes PA. Insights on the use of transgenic mice models in Alzheimer's disease research. Int J Mol Sci. 2024; 25(5): 2805. doi: 10.3390/ijms25052805 38474051 PMC10931675 source

      Section 2.3 says APP and APP/PS models lack neurofibrillary tangles, while its PS19 description reports tau tangles without β-amyloid deposits. These passages support the distinction between amyloid-focused and tau-focused models, but the review does not establish that most preclinical studies used them in isolation; it also describes models combining both pathologies. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Human longitudinal studies show that a markedly increased risk of progression from mild cognitive impairment to AD is largely confined to individuals with concurrent Aβ and tau abnormalities, rather than those with only Aβ or only tau pathology.

    “human longitudinal studies show that a markedly increased risk of progression from mild cognitive impairment to AD is largely confined to individuals with concurrent Aβ and tau abnormalities, rather than those with only Aβ or only tau pathology.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Pascoal TA, Mathotaarachchi S, Shin M, et al. Synergistic interaction between amyloid and tau predicts the progression to dementia. Alzheimers Dement. 2017; 13(6): 644‐ 653. doi: 10.1016/j.jalz.2016.11.005 28024995 source
  • Premisecitation

    A previously published analysis of AMP-AD data identified 30 co-expression modules significantly enriched for DEGs between AD patients and controls.

    “We leveraged a previously published analysis of the AMP‐AD data, which identified 30 co‐expression modules significantly enriched for DEGs between AD patients and controls. 37”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Wan Y‐W, Al‐Ouran R, Mangleburg CG, et al. Meta‐Analysis of the Alzheimer's disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 2020; 32(2): 107908. doi: 10.1016/j.celrep.2020.107908 32668255 PMC7428328 source
  • Findingown data

    PHGgreen was enriched with oligodendrocyte- and myelin-associated genes (Mog, Mag, Cldn11, and Ugt8a), consistent with findings from Wan et al.

    “Notably, PHGgreen was enriched with oligodendrocyte‐ and myelin‐associated genes (Mog, Mag, Cldn11, and Ugt8a; Figure 6F), consistent with findings from Wan et al. 37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Wan Y‐W, Al‐Ouran R, Mangleburg CG, et al. Meta‐Analysis of the Alzheimer's disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 2020; 32(2): 107908. doi: 10.1016/j.celrep.2020.107908 32668255 PMC7428328 source
  • May combine two claims. 50
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Premisecitation

    Exacerbated microgliosis and astrogliosis occur in 5XFAD.

    “as well as exacerbated microgliosis and astrogliosis in 5XFAD. 25 , 57”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [25] Kim B, Dabin LC, Tate MD, et al. Effects of SPI1‐mediated transcriptome remodeling on Alzheimer's disease‐related phenotypes in mouse models of Aβ amyloidosis. Nat Commun. 2024; 15(1): 3996. doi: 10.1038/s41467‐024‐48484‐x 38734693 PMC11088624 source

      The Results section ‘Exacerbation of microgliosis and astrogliosis by Spi1 knockdown’ reports exacerbation in Spi1-knockdown APP/PS1 mice, not 5XFAD mice. In ‘Amelioration of gliosis by Spi1 overexpression,’ the paper measures both forms of gliosis in 5XFAD mice but reports that Spi1 overexpression reduces them; it does not show exacerbation in 5XFAD. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [57] Karahan H, Smith DC, Kim B, et al. Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Abeta amyloidosis. Sci Adv. 2021; 7(45): eabe3954. doi: 10.1126/sciadv.abe3954 34731000 PMC8565913 source

      The Results section, “Plaque-associated microglia are decreased in Abi3−/− mice” (page unavailable), reports no difference in overall microgliosis between Abi3 genotypes on the 5XFAD background; it also finds fewer microglia around plaques after Abi3 deletion. Our copy does not report exacerbated astrogliosis in these mice. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    APPNL-G-F/MAPT do not develop neurofibrillary tangles and neuronal loss until 24 months, and remain transcriptomically undercharacterized.

    “However, APPNL‐G‐F/MAPT do not develop neurofibrillary tangles and neuronal loss until 24 months, 73 and remain transcriptomically undercharacterized.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [73] Saito T, Mihira N, Matsuba Y, et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J Biol Chem. 2019; 294(34): 12754‐ 12765. doi: 10.1074/jbc.RA119.009487 31273083 PMC6709628 source

      In “Humanization of Mapt gene in App KI mice” (page unavailable), the paper reports that APPNL-G-F/MAPT mice had no neurofibrillary tangles at 24 months, contrary to the claimed onset at that age. The “Propagation of AD brain-derived pathological tau proteins” section (page unavailable) also reports no neurodegeneration after pathological tau inoculation. The transcriptomic characterization statement follows the citation and is not attributed to this source. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Alzheimer's disease is characterized by two core biomarkers: amyloid beta plaques and tau neurofibrillary tangles.

    “Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by two core biomarkers: amyloid beta (Aβ) plaques and tau neurofibrillary tangles.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [1] Rosenberg A, Öhlund‐Wistbacka U, Hall A, et al. beta‐amyloid, Tau, neurodegeneration classification and eligibility for anti‐amyloid treatment in a memory clinic population. Neurol. 2022; 99(19): e2102‐ e2113. doi: 10.1212/WNL.0000000000201043 PMC9651451 36130840 source

      The Abstract’s Discussion identifies amyloid-β and tau as core AD biomarkers and says that abnormal levels of both denote AD. The Methods’ Biomarker Assessment describes fluid measurements, however; the passages do not identify plaques and neurofibrillary tangles as the biomarkers themselves. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [2] Jack CR, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024; 20(8): 5143‐ 5169. doi: 10.1002/alz.13859 38934362 PMC11350039 source

      The Biomarker Categorization section identifies Aβ and tau as core biomarker categories, and the Highlights describe AD neuropathologic change as including neuritic plaques and tangles. But the paper distinguishes those pathologic deposits from the biomarker tests that detect or reflect them; it does not call plaques and tangles themselves the two core biomarkers. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [3] Jack CR, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013; 12(2): 207‐ 216. doi: 10.1016/s1474‐4422(12)70291‐0 23332364 PMC3622225 source

      The paper’s Interpretation (page unavailable) discusses LRRK2 variants and Parkinson’s disease, not biomarkers of Alzheimer’s disease. Searches for Alzheimer’s disease, amyloid-beta plaques, tau, and neurofibrillary tangles found no passage in our copy addressing the claim. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Growing evidence indicates a critical interplay between Aβ and tau pathologies that drives disease progression, potentially through synapses and glial activation.

    “A growing body of evidence highlights the critical interplay between these pathologies, potentially through synapses and glial activation, that drives disease progression.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [4] Busche MA, Hyman BT. Synergy between amyloid‐β and tau in Alzheimer's disease. Nat Neurosci. 2020; 23(10): 1183‐ 1193. doi: 10.1038/s41593‐020‐0687‐6 32778792 PMC11831977 source
    • cites [5] Stancu I‐C, Vasconcelos B, Terwel D, Dewachter I. Models of β‐amyloid induced Tau‐pathology: the long and “folded” road to understand the mechanism. Mol Neurodegen. 2014; 9(1): 51. doi: 10.1186/1750‐1326‐9‐51 PMC4255655 25407337 source
    • cites [6] Ittner LM, Ke YD, Delerue F, et al. Dendritic function of tau mediates amyloid‐β toxicity in Alzheimer's disease mouse models. Cell. 2010; 142(3): 387‐ 397. doi: 10.1016/j.cell.2010.06.036 20655099 source

  • May combine two claims.

    Findingown data

    Microglial and oligodendrocyte clusters associated with the immune module emerged as key contributors, exhibiting synaptic suppression and immune modulation.

    “Microglial and oligodendrocyte clusters associated with the immune module consistently emerged as key contributors, exhibiting synaptic suppression in differential expression analyses and immune modulation inferred by CellChat. 24”
    • Also stated in: § RESULTS · plain
      “These programs included disruption of glial lipid metabolism and immune pathways at the network level, alongside immune and synaptic alterations coordinated between microglia and oligodendrocytes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Jin S, Guerrero‐Juarez CF, Zhang L, et al. Inference and analysis of cell‐cell communication using CellChat. Nat Commun. 2021; 12(1): 1088. doi: 10.1038/s41467‐021‐21246‐9 33597522 PMC7889871 source

  • May combine two claims.

    Study design and conductcitation

    The study used 9-month-old animals, when each model exhibits robust amyloid and/or tau pathology, and included equal numbers of males and females.

    “We used 9‐month‐old animals, when each model exhibits robust amyloid and/or tau pathology, 11 , 12 , 43 and included equal numbers of males and females.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [11] Oakley H, Cole SL, Logan S, et al. Intraneuronal β‐Amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006; 26(40): 10129‐ 10140. doi: 10.1523/jneurosci.1202‐06.2006 17021169 PMC6674618 source
    • cites [12] Yoshiyama Y, Higuchi M, Zhang B, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007; 53(3): 337‐ 351. doi: 10.1016/j.neuron.2007.01.010 17270732 source
    • cites [43] Saul A, Sprenger F, Bayer TA, Wirths O. Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease. Neurobiol Aging. 2013; 34(11): 2564‐ 2573. doi: 10.1016/j.neurobiolaging.2013.05.003 23747045 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Single-cell and single-nucleus RNA sequencing studies have identified multiple disease-associated glial subtypes with distinct transcriptional states and selectively vulnerable neuronal populations in amyloidosis or tauopathy models.

    “These studies have identified multiple disease‐associated glial subtypes with distinct transcriptional states and selectively vulnerable neuronal populations in amyloidosis models 16 , 17 , 18 or tauopathy models. 19 , 20 , 21”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [16] Keren‐Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017; 169(7): 1276‐ 1290.e17. doi: 10.1016/j.cell.2017.05.018 28602351 source
    • cites [17] Park H, Cho B, Kim H, et al. Single‐cell RNA‐sequencing identifies disease‐associated oligodendrocytes in male APP NL‐G‐F and 5XFAD mice. Nat Commun. 2023; 14(1): 802. doi: 10.1038/s41467‐023‐36519‐8 36781874 PMC9925742 source

      The Abstract (page unavailable) reports a disease-associated oligodendrocyte subpopulation identified by single-cell RNA sequencing in amyloidosis mouse models, and the Introduction describes other disease-associated glial subtypes. The paper does not identify selectively vulnerable neuronal populations; its contribution supports the glial part of the amyloidosis claim, not that neuronal part. The tauopathy portion is attached to other citations. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] Habib N, McCabe C, Medina S, et al. Disease‐associated astrocytes in Alzheimer's disease and aging. Nat Neurosci. 2020; 23(6): 701‐ 706. doi: 10.1038/s41593‐020‐0624‐8 32341542 PMC9262034 source

      The Results passages in our copy (section labeled Abstract; page unavailable) identify disease-associated astrocytes with distinct transcriptional states in 5xFAD mice and report changes in disease-associated microglia. They also report a reduced proportion of recently activated pyramidal neurons, but do not establish that a neuronal population is selectively vulnerable. This paper studies an amyloidosis model, not a tauopathy model. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    These modules were grouped into five consensus clusters and annotated using Reactome, representing conserved AD-related molecular signatures across cohorts and brain regions.

    “These modules were grouped into five consensus clusters and annotated using Reactome, representing conserved AD‐related molecular signatures across cohorts and brain regions. 37 , 41 , 51”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [37] Wan Y‐W, Al‐Ouran R, Mangleburg CG, et al. Meta‐Analysis of the Alzheimer's disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 2020; 32(2): 107908. doi: 10.1016/j.celrep.2020.107908 32668255 PMC7428328 source

      The Results section, “A Consensus Atlas of AD-Associated Transcriptional Modules from Human Brain,” says that 30 AD-associated modules formed five consensus clusters preserved across studies and brain regions. It also reports enrichment for biological processes, but the Methods section lists several annotation resources without saying that the clusters were annotated using Reactome; the only explicit Reactome mention is in the title of a cited PANTHER paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [41] Preuss C, Pandey R, Piazza E, et al. A novel systems biology approach to evaluate mouse models of late‐onset Alzheimer's disease. Mol Neurodegen. 2020; 15(1): 67. doi: 10.1186/s13024‐020‐00412‐5 PMC7656729 33172468 source
    • cites [51] Haw R, Hermjakob H, D'Eustachio P, Stein L. Reactome pathway analysis to enrich biological discovery in proteomics data sets. Proteomics. 2011; 11(18): 3598‐ 3613. doi: 10.1002/pmic.201100066 21751369 PMC4617659 source

  • May combine two claims.

    Findingown data

    O_3 cluster was distinctly enriched for marker genes of disease-associated oligodendrocytes (DAO) compared to other oligodendrocyte clusters, with DAO signature most prominently expressed in 5XFAD;PS19.

    “Moreover, the O_3 cluster was distinctly enriched for marker genes of disease‐associated oligodendrocytes (DAO) 17 , 46 compared to other oligodendrocyte clusters, with the DAO signature most prominently expressed in the 5XFAD;PS19 model (Figure S4A,B in supporting information).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [17] Park H, Cho B, Kim H, et al. Single‐cell RNA‐sequencing identifies disease‐associated oligodendrocytes in male APP NL‐G‐F and 5XFAD mice. Nat Commun. 2023; 14(1): 802. doi: 10.1038/s41467‐023‐36519‐8 36781874 PMC9925742 source
    • cites [46] Kenigsbuch M, Bost P, Halevi S, et al. A shared disease‐associated oligodendrocyte signature among multiple CNS pathologies. Nat Neurosci. 2022; 25(7): 876‐ 886. doi: 10.1038/s41593‐022‐01104‐7 35760863 PMC9724210 source
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

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

    Premisecitation

    VISTA functions as an inhibitory immune checkpoint, attenuating T-cell activation and contributing to immune homeostasis.

    “VISTA functions as an inhibitory immune checkpoint, attenuating T‐cell activation and contributing to immune homeostasis. 49 , 50”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [49] Borggrewe M, Grit C, Den Dunnen WFA, et al. VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases. Glia. 2018; 66(12): 2645‐ 2658. doi: 10.1002/glia.23517 30306644 PMC6585704 source
    • cites [50] Huang X, Zhang X, Li E, et al. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol. 2020; 13(1): 83. doi: 10.1186/s13045‐020‐00917‐y 32600443 PMC7325042 source

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

    Premisecitation

    PROS1 acts as an anti-inflammatory mediator by activating TAM (TYRO3, AXL, and MERTK) receptors, facilitating the phagocytic clearance of apoptotic cells and dampening inflammation.

    “PROS1 acts as an anti‐inflammatory mediator by activating TAM (TYRO3, AXL, and MERTK) receptors, facilitating the phagocytic clearance of apoptotic cells and dampening inflammation. 48”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Burstyn‐Cohen T, Hochberg A. TAM signaling in the nervous system. Brain Plast. 2021; 7(1): 33‐ 46. doi: 10.3233/BPL‐210125 34631419 PMC8461745 source

      The neuroimmune-interface section says PROS1 helps bridge apoptotic cells to phagocytes, promoting their clearance and anti-inflammatory signaling. But the receptors-and-ligands section explicitly says PROS1 activates TYRO3 and MERTK, not AXL; the claim incorrectly includes AXL among the receptors PROS1 activates. No page number is available in our copy. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Astrocytic lipid metabolism pathways are downregulated in the APP/PS1 amyloidosis model.

    “This finding aligns with reports that astrocytic lipid metabolism pathways are downregulated in the APP/PS1 amyloidosis model. 52”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Zhong J, Li M, Dai Z, Wan J. Multi‐omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease. Neurochem Int. 2025; 190: 106049. doi: 10.1016/j.neuint.2025.106049 40889558 source

  • May combine two claims.

    Premisecitation

    Like DAM, which appears in 5XFAD at 1 to 2 months of age, DAO is also enriched near Aβ plaques at 9 to 10 months of age.

    “Like DAM, which appears in 5XFAD at 1 to 2 months of age, DAO is also enriched near Aβ plaques at 9 to 10 months of age. 17 , 46”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] Park H, Cho B, Kim H, et al. Single‐cell RNA‐sequencing identifies disease‐associated oligodendrocytes in male APP NL‐G‐F and 5XFAD mice. Nat Commun. 2023; 14(1): 802. doi: 10.1038/s41467‐023‐36519‐8 36781874 PMC9925742 source

      The Results section, “Molecular signature of disease-associated oligodendrocytes” (Fig. 3h–i; page unavailable), reports DAOs adjacent to Aβ plaques, but the pictured mice were 6-month-old AppNL-G-F mice, not 9–10 months old. Our copy does not establish that DAM appears in 5XFAD mice at 1–2 months of age. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [46] Kenigsbuch M, Bost P, Halevi S, et al. A shared disease‐associated oligodendrocyte signature among multiple CNS pathologies. Nat Neurosci. 2022; 25(7): 876‐ 886. doi: 10.1038/s41593‐022‐01104‐7 35760863 PMC9724210 source

      The Results section on identifying disease-associated oligodendrocytes says DAM appear in 5xFAD mice at 1–2 months and the oligodendrocyte state, called DOLs in this paper, is detected around 9–10 months. The spatial-analysis Results show these cells near Aβ plaques, but that analysis used 16-month-old mice; it does not establish plaque proximity specifically at 9–10 months. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    More physiological double knock-in models express humanized mutant APP and MAPT under endogenous promoters.

    “More physiological double knock‐in models express humanized mutant APP and MAPT under endogenous promoters. 73 , 74”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [73] Saito T, Mihira N, Matsuba Y, et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J Biol Chem. 2019; 294(34): 12754‐ 12765. doi: 10.1074/jbc.RA119.009487 31273083 PMC6709628 source

      The Abstract describes crossing humanized MAPT knock-in mice with App knock-in mice to produce double knock-in mice. The Mutant mice section identifies mutations in the App mice, and the Discussion contrasts the knock-in approach with transgenic overexpression. Our copy does not establish that APP itself was humanized, so that part of the claim remains unsupported. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [74] Hashimoto S, Matsuba Y, Kamano N, et al. Tau binding protein CAPON induces tau aggregation and neurodegeneration. Nat Commun. 2019; 10(1): 2394. doi: 10.1038/s41467‐019‐10278‐x 31160584 PMC6546774 source

      The Introduction describes double-knock-in mice made by crossing an App knock-in carrying familial Alzheimer’s mutations with a human MAPT knock-in. The Methods say human MAPT replaces mouse Mapt at its native locus. However, the Introduction explicitly says the human tau is wild-type, so the claim is unsupported if “mutant” is intended to describe MAPT as well as APP. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Amyloid mouse models, including 5XFAD, capture approximately 30% of human AD-associated protein alterations.

    “Nevertheless, proteomics comparison demonstrated that amyloid mouse models, including 5XFAD, capture ≈ 30% of human AD‐associated protein alterations. 72”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [72] Yarbro JM, Han X, Dasgupta A, et al. Human and mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome. Nat Commun. 2025; 16(1): 1533. doi: 10.1038/s41467‐025‐56853‐3 39934151 PMC11814087 source

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

    Premisecitation

    Synaptic dysfunction is a hallmark of AD and has been reported in both combined pathology mouse models and human AD brains.

    “Synaptic dysfunction is a hallmark of AD and has been reported in both combined pathology mouse models and human AD brains. 43 , 58 , 59”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [43] Saul A, Sprenger F, Bayer TA, Wirths O. Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease. Neurobiol Aging. 2013; 34(11): 2564‐ 2573. doi: 10.1016/j.neurobiolaging.2013.05.003 23747045 source
    • cites [58] Stancu I‐C, Ris L, Vasconcelos B, et al. Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease. FASEB J. 2014; 28(6): 2620‐ 2631. doi: 10.1096/fj.13‐246702 24604080 source
    • cites [59] Pickett EK, Herrmann AG, McQueen J, et al. Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer's disease. Cell Rep. 2019; 29(11): 3592‐ 3604.e5. doi: 10.1016/j.celrep.2019.11.044 31825838 PMC6915767 source

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

    Premisecitation

    A prior study reported a 3- to 4-fold increase in the number of neurons expressing cell cycle reentry programs in advanced AD patients compared to healthy individuals.

    “Additionally, a prior study reported a 3‐ to 4‐fold increase in the number of neurons expressing cell cycle reentry programs in advanced AD patients compared to healthy individuals. 69”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [69] Meir R, Schwartz G, Adam M, et al. Early neuronal reprogramming and cell cycle reentry shape Alzheimer's disease progression. Biorxiv. Preprint published online Jun 6, 2025. doi: 10.1101/2025.06.04.653670 source

      The section ‘Neurons converge to distinct programs of stress/apoptosis or cell-cycle reentry’ reports a 3- to 4-fold increase in advanced AD compared with healthy individuals. It specifies that the increase occurred in inhibitory and deep-layer (L4–6) excitatory neurons, but not L2–3 neurons; the citing sentence omits that limitation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Altered lipid metabolites and relevant gene expression occur in human AD.

    “It further corresponds with altered lipid metabolites and relevant gene expression in human AD. 53 , 54 , 55”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [53] Varma VR, Büşra Lüleci H, Oommen AM, et al. Abnormal brain cholesterol homeostasis in Alzheimer's disease—a targeted metabolomic and transcriptomic study. npj Aging. 2021; 7(1): 11. doi: 10.1038/s41514‐021‐00064‐9 PMC8169871 34075056 source
    • cites [54] Ju Y, Li S, Kong X, Zhao Q. Exploring fatty acid metabolism in Alzheimer's disease: the key role of CPT1A. Sci Rep. 2024; 14(1): 31483. doi: 10.1038/s41598‐024‐82999‐z 39733087 PMC11682225 source
    • cites [55] Snowden SG, Ebshiana AA, Hye A, et al. Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: a nontargeted metabolomic study. PLoS Med. 2017; 14(3): e1002266. doi: 10.1371/journal.pmed.1002266 28323825 PMC5360226 source

      The Results report altered levels of several unsaturated fatty acids in human AD brain tissue compared with controls, supporting the lipid-metabolite portion of the claim. The paper reports metabolite profiling, but the passages do not establish altered expression of relevant genes (searched: gene expression; gene expression lipid metabolism). (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Parental lines rely on transgenic overexpression of familial AD or FTD mutations and do not fully recapitulate the slow accumulation of amyloid and tau in humans.

    “First, although 5XFAD;PS19 provides an experimentally tractable system for studying Aβ–tau interactions, parental lines rely on transgenic overexpression of familial AD or frontotemporal dementia (FTD) mutations and do not fully recapitulate the slow accumulation of amyloid and tau in humans. 70 , 71”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [70] Sasaguri H, Nilsson P, Hashimoto S, et al. APPmouse models for Alzheimer's disease preclinical studies. EMBO J. 2017; 36(17): 2473‐ 2487. doi: 10.15252/embj.201797397 28768718 PMC5579350 source

      The First-generation mouse models section identifies 5XFAD as carrying APP and PS1 familial-AD transgenes, and describes overexpressed mutant tau in another model as deriving from frontotemporal dementia rather than AD. It reports Aβ pathology in 5XFAD by two months, while the Limitations of second-generation mouse models section says human Aβ amyloidosis may take more than two decades to induce cortical tauopathy. Our copy does not identify PS19 specifically, so it does not establish that both parental lines have the stated characteristics. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [71] Saito T, Matsuba Y, Yamazaki N, Hashimoto S, Saido TC. Calpain activation in Alzheimer's model mice is an artifact of APP and presenilin overexpression. J Neurosci. 2016; 36(38): 9933‐ 9936. doi: 10.1523/JNEUROSCI.1907‐16.2016 27656030 PMC5030353 source

      The Introduction (page not specified in our copy) identifies 5XFAD mice as transgenic mice overexpressing APP and presenilin with five familial AD-associated mutations. The Results and Discussion describe artifacts of APP overexpression that limit these models' resemblance to AD. The paper does not identify PS19 or an FTD mutation, or assess whether the parental lines reproduce the slow accumulation of both amyloid and tau in humans. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    In the PROS pathway, PROS1 acts as a ligand for MERTK, promoting phagocytosis and enhancing astrocyte-mediated clearance of apoptotic cells in a CNS demyelination model.

    “In the PROS pathway, PROS1 acts as a ligand for MERTK, promoting phagocytosis and enhancing astrocyte‐mediated clearance of apoptotic cells in a CNS demyelination model. 67”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [67] Hou J, Zhou Y, Cai Z, et al. Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination. Cell Rep. 2023; 42(4): 112293. doi: 10.1016/j.celrep.2023.112293 36952346 PMC10511667 source

      The Results section reports that PROS1 enhanced astrocyte phagocytosis of apoptotic thymocytes in a coculture assay and says this supports a role for PROS1–AXL/MERTK interactions in clearance in the CPZ demyelination model. It does not show that MERTK specifically mediated the effect or directly demonstrate enhanced astrocyte clearance in vivo. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    VISTA has been reported to be upregulated in microglia surrounding Aβ plaques in AD but downregulated in chronically inflamed lesions in multiple sclerosis.

    “VISTA has been reported to be upregulated in microglia surrounding Aβ plaques in AD but downregulated in chronically inflamed lesions in multiple sclerosis, 49”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Borggrewe M, Grit C, Den Dunnen WFA, et al. VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases. Glia. 2018; 66(12): 2645‐ 2658. doi: 10.1002/glia.23517 30306644 PMC6585704 source

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

    Premisecitation

    A snRNA-seq study in human AD reported downregulation of synaptic cell adhesion-related gene expression and enrichment terms in an oligodendrocyte cluster.

    “A snRNA‐seq study in human AD also reported downregulation of synaptic cell adhesion–related gene expression and enrichment terms in an oligodendrocyte cluster. 65 , 66”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [65] Sadick JS, O'Dea MR, Hasel P, Dykstra T, Faustin A, Liddelow SA. Astrocytes and oligodendrocytes undergo subtype‐specific transcriptional changes in Alzheimer's disease. Neuron. 2022; 110(11): 1788‐ 1805.e10. doi: 10.1016/j.neuron.2022.03.008 35381189 PMC9167747 source
    • cites [66] Yang S, Park JH, Lu HC. Axonal energy metabolism, and the effects in aging and neurodegenerative diseases. Mol Neurodegener. 2023; 18(1): 49. doi: 10.1186/s13024‐023‐00634‐3 37475056 PMC10357692 source

      The Background section reports that a subtype-specific transcriptomic analysis of oligodendrocytes in human AD brains found downregulated synaptic cell adhesion molecules in a subcluster. Our copy does not specify that this was an snRNA-seq study or report downregulated enrichment terms. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Oligodendrocytes may modulate axon myelination in response to synaptic input, given their expression of glutamate receptor genes in mice and of excitatory synaptic proteins in zebrafish.

    “Oligodendrocytes may modulate axon myelination in response to synaptic input, given their expression of glutamate receptor genes in mice 63 and of excitatory synaptic proteins in zebrafish. 64”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [63] Marques S, Zeisel A, Codeluppi S, et al. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science. 2016; 352(6291): 1326‐ 1329. doi: 10.1126/science.aaf6463 27284195 PMC5221728 source
    • cites [64] Hughes AN, Appel B. Oligodendrocytes express synaptic proteins that modulate myelin sheath formation. Nat Commun. 2019; 10(1): 4125. doi: 10.1038/s41467‐019‐12059‐y 31511515 PMC6739339 source

  • May combine two claims.

    Findingown data

    Two transcriptional programs emerged with combined Aβ and tau pathology: glial lipid metabolic dysregulation and coordinated microglial-oligodendrocyte responses involving immune and synaptic alterations; both pathways were less apparent in single-pathology models.

    “Two transcriptional programs emerged with combined Aβ and tau pathology: glial lipid metabolic dysregulation and coordinated microglial–oligodendrocyte responses involving immune and synaptic alterations. Both pathways were less apparent in single‐pathology models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the 5XFAD;PS19 model, there was a decrease in excitatory neurons and astrocytes and an increase in oligodendrocytes and microglia.

    “Specifically, in the 5XFAD;PS19 model, there was a decrease in excitatory neurons and astrocytes and an increase in oligodendrocytes and microglia (Figure 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 5XFAD;PS19 model exhibited significant alterations in cell-type proportions compared to wild type, whereas 5XFAD or PS19 alone did not.

    “The 5XFAD;PS19 model exhibited significant alterations in cell‐type proportions compared to WT, whereas 5XFAD or PS19 alone did not (Figure 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mod5 and Mod7 were associated with glutamatergic and GABAergic synaptic transmission, respectively.

    “GO analysis revealed that Mod5 and Mod7 were associated with glutamatergic and GABAergic synaptic transmission, respectively (Figure S2B,C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In PS19 mice, Mod4 and Mod9 alterations were each restricted to a single cluster.

    “Mod4 and Mod9 alterations were each restricted to a single cluster”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    Microglial clusters showed a similar trend of increase in 5XFAD;PS19 mice, but this did not reach statistical significance.

    “While microglial clusters showed a similar trend of increase in 5XFAD;PS19 mice, this did not reach statistical significance (Figure 1I).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ExN_11 excitatory neurons and O_3 oligodendrocytes exhibited significant changes in 5XFAD;PS19 versus wild type.

    “Notably, ExN_11 (excitatory neurons) and O_3 (oligodendrocytes) exhibited significant changes in 5XFAD;PS19 versus WT (Figure 1G,H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genotype-specific pathology was validated: 5XFAD exhibited elevated Aβ42, PS19 presented increased phosphorylated tau at threonine 231, and 5XFAD;PS19 harbored both pathological features, confirming it as a combined-pathology model.

    “Genotype‐specific pathology was validated by quantifying well‐established pathological forms of Aβ and tau levels: 5XFAD exhibited elevated Aβ42, PS19 presented increased phosphorylated tau at threonine 231 (p‐tau‐T231), and 5XFAD;PS19 harbored both pathological features, confirming it as a combined‐pathology model (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mod6 upregulation intensified in 5XFAD;PS19, with additional increase in microglial (M_2) and oligodendrocyte (O_3) clusters uniquely in 5XFAD;PS19.

    “Mod6 upregulation also intensified, with an additional increase in microglial (M_2) and oligodendrocyte (O_3) clusters uniquely in 5XFAD;PS19 (Figure 2F).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

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

    Findingown data

    Enrichment analysis of Module 2 and Module 6 was performed based on WikiPathways 2024 Mouse.

    “G–H, Enrichment analysis of Module 2 (G) and Module 6 (H) based on WikiPathways 2024 Mouse.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mod12 showed only modest changes in PS19 but became strongly upregulated across many clusters in the combined model.

    “Similarly, Mod12 showed only modest changes in PS19 (Figure 2E) but became strongly upregulated across many clusters in the combined model (Figure 2F).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.

  • May combine two claims.

    Findingown data

    DEGs from 5XFAD;PS19 model exhibited the strongest significant alignment with DEGs from human AD transcriptomes, particularly in modules related to immune response (Cluster B), neuronal signaling (Cluster C), mitotic cell cycle or nonsense-mediated mRNA decay pathways (Cluster D), and organelle biogenesis or cellular stress response pathways (Cluster E).

    “Correlation analysis revealed that DEGs from the 5XFAD;PS19 model exhibited the strongest significant alignment with DEGs from human AD transcriptomes (Table S6 in supporting information), particularly in modules related to immune response (Cluster B), neuronal signaling (Cluster C), mitotic cell cycle or nonsense‐mediated mRNA decay pathways (Cluster D), and organelle biogenesis or cellular stres”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.

  • May combine two claims.

    Findingown data

    In M_1, actin-associated gene Dpysl3 was downregulated, whereas lysosomal genes Ctsh and Cst7 were upregulated in 5XFAD;PS19 relative to WT.

    “In the M_1 cluster, the actin‐associated gene Dpysl3 was downregulated, whereas the lysosomal genes Ctsh and Cst7 were upregulated in 5XFAD;PS19 relative to WT (Figure 3L).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    In O_2, immune gene Ptprc (Cd45) was elevated, whereas synaptic genes including Rph3a and Stxbp1 were reduced in 5XFAD;PS19 compared to WT.

    “In the O_2 cluster, the immune gene Ptprc (Cd45) was elevated, whereas synaptic genes including Rph3a and Stxbp1 were reduced (Figure 3K).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    Outgoing signaling increased from M_1 and O_3 clusters, with broader reception across both neuronal and glial clusters.

    “Outgoing signaling increased from M_1 and O_3 clusters, with broader reception across both neuronal and glial clusters (Figures 5I,J, and S6B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.
    • Rests on an assumption: CellChat-inferred ligand–receptor interactions reflect actual intercellular signaling in the brain.

  • May combine two claims.

    Findingown data

    Enrichment analysis of all DEGs in 5XFAD;PS19 mice revealed immune signaling in InN_1, mitochondrial and synaptic function in O_2, and immune-related functions in M_1.

    “Enrichment analysis of all DEGs in 5XFAD;PS19 mice revealed immune signaling in InN_1 (Figure 3G), mitochondrial and synaptic function in O_2 (Figure 3H), and immune‐related functions in M_1 (Figure 3I).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    Expression of hdWGCNA Mod6 was enriched in both M_2 and O_3, with especially strong upregulation in 5XFAD;PS19.

    “Notably, the expression of hdWGCNA Mod6 was enriched in both M_2 and O_3, with especially strong upregulation in 5XFAD;PS19 (Figure 2F)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    In InN_1, immune-related genes Kmo and Stat4 were upregulated, whereas Ldlr was downregulated in 5XFAD;PS19 compared to WT.

    “In the InN_1 cluster, immune‐related genes such as Kmo and Stat4 were upregulated, whereas Ldlr was downregulated in 5XFAD;PS19 compared to WT (Figure 3J).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    In WT controls, PROS signaling was driven mostly by InN_8 and M_2, whereas in 5XFAD;PS19, outgoing signals increased from InN_8, O_3, M_1, M_2, and EC_2.

    “In WT controls, PROS signaling was driven mostly by InN_8 and M_2, whereas in 5XFAD;PS19, outgoing signals increased from InN_8, O_3, M_1, M_2, and EC_2 (Figures 5F,G, and S6A in supporting information).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.
    • Rests on an assumption: CellChat-inferred ligand–receptor interactions reflect actual intercellular signaling in the brain.

  • May combine two claims.

    Findingown data

    In M_2 cluster, 5XFAD;PS19 shared 177 DEGs with 5XFAD but only 1 with PS19.

    “Notably, in the M_2 cluster, 5XFAD;PS19 shared 177 DEGs with 5XFAD but only 1 with PS19 (Figure 4D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    M_2 microglia and O_3 oligodendrocytes are overrepresented in the 5XFAD;PS19 model compared to WT.

    “we focused on M_2 microglia and O_3 oligodendrocytes, two clusters overrepresented in the 5XFAD;PS19 model compared to WT.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Findingown data

    Both M_2 and O_3 exhibited suppression of synaptic gene expression, with enrichment terms related to synaptic transmission.

    “Interestingly, both M_2 and O_3 exhibited the suppression of synaptic gene expression (Figure 4H,I), with enrichment terms related to synaptic transmission (Figure 4F,G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In our analysis, 5XFAD;PS19 demonstrated a correlation with human data comparable to 5XFAD in the immune system but exhibited stronger alignment in extracellular matrix organization, neuronal system (synapse), and cell cycle consensus clusters.

    “In our analysis, 5XFAD;PS19 demonstrated a correlation with human data comparable to 5XFAD in the immune system but exhibited stronger alignment in extracellular matrix organization, neuronal system (synapse), and cell cycle consensus clusters (Figure 6C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The lipid metabolism module (Mod2) was moderately downregulated in some astrocyte clusters of 5XFAD, but not in PS19.

    “The lipid metabolism module (Mod2) was moderately downregulated in some astrocyte clusters of 5XFAD, but not in PS19.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In our data, the combined pathology increased outgoing signals from M_1, M_2, and O_3 and elevated incoming signals to astrocyte clusters.

    “In our data, the combined pathology increased outgoing signals from M_1, M_2, and O_3 and elevated incoming signals to astrocyte clusters (Figures 5G and S6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The machine-assisted nuclei isolation protocol minimizes ambient RNA contamination and enables capture of large numbers of high-quality nuclei across diverse cell types.

    “Our machine‐assisted nuclei isolation protocol minimizes ambient RNA contamination 22 and enables the capture of large numbers of high‐quality nuclei across diverse cell types.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Kersey HN, Acri DJ, Dabin LC, et al. Comparative analysis of nuclei isolation methods for brain single‐nucleus RNA sequencing. Biorxiv. Preprint published online March 26, 2025. doi: https://www.cell.com/cell‐reports‐methods/fulltext/S2667‐2375(26)00037‐8 PMC13030979 41875869 source

  • May combine two claims.

    Study design and conductown data

    Quality metrics demonstrated robust data with a median of approximately 3000 unique genes per nucleus, more than 6000 transcripts per nucleus, and less than 1% mitochondrial reads.

    “Quality metrics demonstrated robust data with a median of ≈ 3000 unique genes per nucleus, > 6000 transcripts per nucleus, and < 1% mitochondrial reads (Figure S1A–C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Automation minimized technical variability and ensured greater consistency in key quality control metrics.

    “Automation minimized technical variability and ensured greater consistency in key quality control metrics (Figure S1 in supporting information).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    After preprocessing, 170,918 high-quality nuclei were retained for downstream analysis.

    “After preprocessing, a total of 170,918 high‐quality nuclei were retained for downstream analysis.”
    • Also stated in: § Distinct cell‐population changes in the combined‐pathology mouse model, but not in the Aβ amyloidosis or tauopathy models · plain
      “After this preprocessing pipeline, we retained 170,918 high‐quality nuclei.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The combined pathology model shows substantial alterations in functional gene co-expression networks in both glia and neurons, with glial modules exhibiting particularly pronounced differential regulation.

    “Together, these findings highlight substantial alterations in functional gene co‐expression networks in both glia and neurons of the combined pathology model, with glial modules exhibiting particularly pronounced differential regulation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.

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

    Study design and conductown data

    Key marker genes for each cell type were highly expressed in their respective clusters.

    “Key marker genes for each cell type were highly expressed in their respective clusters (Figure 1E and Table S1 in supporting information).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Anti-Aβ therapies alone may offer limited benefit once symptoms emerge.

    “Busche and Hyman 4 argued that anti‐Aβ therapies alone may offer limited benefit once symptoms emerge, underscoring the need to consider the synergistic relationship between Aβ and tau when developing therapeutics.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Busche and Hyman 4

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

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationnone given

    The study provides a high-quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network-level systems pharmacology approach.

    “Beyond benchmarking mouse models, this study provides a high‐quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network‐level systems pharmacology approach.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Combined pathology induces exclusive transcriptional alterations, not observed in single-pathology mouse models, with substantial contributions from inhibitory neurons, oligodendrocytes, and microglia.

    “Together, differential gene expression analyses demonstrated that combined pathology induces exclusive transcriptional alterations, not observed in single‐pathology mouse models (amyloid only or tau only), with substantial contributions from inhibitory neurons, oligodendrocytes, and microglia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Interpretationown data

    This increase was partially driven by microglial and oligodendrocyte clusters, which seem to respond to combined pathology by upregulating immune-modulatory signaling, particularly via anti-inflammatory and immunosuppressive pathways.

    “This increase was partially driven by microglial and oligodendrocyte clusters, which seem to respond to combined pathology by upregulating immune‐modulatory signaling, particularly via anti‐inflammatory and immunosuppressive pathways.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.
    • Rests on an assumption: CellChat-inferred ligand–receptor interactions reflect actual intercellular signaling in the brain.

  • May combine two claims.

    Interpretationown data

    The combined pathology featured widespread downregulation of a lipid metabolism-related gene module and upregulation of an immune-related gene module, alongside suppressed synaptic transmission and coordinated immune responses involving both microglia and oligodendrocytes.

    “Notably, the combined pathology featured widespread downregulation of a lipid metabolism‐related gene module and upregulation of an immune‐related gene module (Figure 2F–H), alongside suppressed synaptic transmission (Figure 4F–I) and coordinated immune responses (Figure 5D–J) involving both microglia and oligodendrocytes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.

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

    Interpretationreasoning

    The unique upregulation of Hif1a and ApoE potentially reflects a compensatory or stress-responsive mechanism.

    “potentially reflecting a compensatory or stress‐responsive mechanism (Figures 4H and S4F).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.
    • Rests on an assumption: The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

  • May combine two claims.

    Interpretationown data

    This resource study reveals two distinct transcriptional programs that emerge prominently when amyloid and tau pathologies coexist: disruption of glial lipid metabolic networks and coordinated microglial-oligodendrocyte responses involving immune and synaptic alterations.

    “This resource study reveals two distinct transcriptional programs that emerge prominently when amyloid and tau pathologies coexist: disruption of glial lipid metabolic networks and coordinated microglial–oligodendrocyte responses involving immune and synaptic alterations.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.

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

    Study design and conductnone given

    The cross-species comparison is constrained by differences in tissue context, disease staging, and analytical framework.

    “Third, the cross‐species comparison is constrained by differences in tissue context, disease staging, and analytical framework.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    CellChat inferences represent computationally derived communication probabilities from gene expression data and a curated ligand-receptor database.

    “Second, CellChat inferences represent computationally derived communication probabilities from gene expression data and a curated ligand‐receptor database.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The resource resolves cell type-specific network changes, shared versus pathology-specific responses, and candidate intercellular signaling pathways, enabling network-based target prioritization, identification of multicellular intervention points, and integration with human genetic and pharmacologic evidence.

    “It resolves cell type–specific network changes, shared versus pathology‐specific responses, and candidate intercellular signaling pathways, enabling network‐based target prioritization, identification of multicellular intervention points, and integration with human genetic and pharmacologic evidence.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To mitigate gene-level and species-specific differences, the authors focused on conserved, disease-relevant pathway- and biodomain-level concordance.

    “To mitigate gene‐level and species‐specific differences, we focused on conserved, disease‐relevant pathway‐ and biodomain‐level concordance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    This resource offers a foundation for systems-level therapeutic discovery in AD.

    “More broadly, this resource offers a foundation for systems‐level therapeutic discovery in AD.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    CellChat does not capture the full complexity of in vivo signaling dynamics, including post-translational regulation and spatial constraints.

    “CellChat does not capture the full complexity of in vivo signaling dynamics, including post‐translational regulation and spatial constraints.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Our snRNA-seq dataset is publicly available and can be queried to examine cell type-specific transcriptomic changes attributable to Aβ, tau, or their interaction.

    “To further support the research community, our snRNA‐seq dataset is publicly available and can be queried to examine cell type–specific transcriptomic changes attributable to Aβ, tau, or their interaction.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Oligodendrocytes crosstalk with microglia, expressing innate immune receptors and modulating CNS immunity through cytokine signaling.

    “Oligodendrocytes are also known to crosstalk with microglia, expressing innate immune receptors and modulating central nervous system (CNS) immunity through cytokine signaling. 62”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Peferoen L, Kipp M, Van Der Valk P, Van Noort JM, Amor S. Oligodendrocyte‐microglia cross‐talk in the central nervous system. Immunology. 2014; 141(3): 302‐ 313. doi: 10.1111/imm.12163 23981039 PMC3930369 source
69 of 69

  • The paper relies on this without support.

    A gap exists in understanding how Aβ and tau co-occurrence drives transcriptional changes across cell types and coordinated gene networks.

    “However, it remains unclear how the co‐occurrence of Aβ and tau drives transcriptional changes across different cell types, both in the expression level of individual genes and coordinated gene networks.”

  • The paper relies on this without support.

    Direct transcriptomic alignment of mouse models with human AD signatures has rarely been demonstrated previously.

    “Moreover, direct transcriptomic alignment of mouse models with human AD signatures, vital for translational modeling, has rarely been demonstrated previously.”

  • The paper relies on this without support.

    The 5XFAD;PS19 mouse model has combined amyloid and tau pathologies.

    “combined amyloid and tau pathologies”

  • The paper relies on this without support.

    The snRNA-seq clusters analyzed correspond to the annotated brain cell types and states.

    “we focused on M_2 microglia and O_3 oligodendrocytes”

  • The paper relies on this without support.

    CellChat-inferred ligand–receptor interactions reflect actual intercellular signaling in the brain.

    “we applied CellChat 24 to infer ligand–receptor interactions across genotypes”
5 of 5

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.

  • Figure 2B is described as both a cell-type UMAP and a module-color plot

    Minor

    The Figure 2 caption identifies panel B as a UMAP of eight cell types, but later says it shows the module colors used for the enrichment bars. The caption instead identifies panel A as the module feature plots.

  • Figure S3E is assigned to two different cell types

    Minor

    The results text cites Figure S3E for both oligodendrocyte and endothelial-cell DEG plots, making the panel assignment inconsistent.

2 of 2

Cites

Flagged first, then by citations

Authors
Park, J. H., Kim, B., Al‐Amin, M. M., Tate, M. D., Sharify, A. D., John, S. K., Karahan, H., Lu, H., Dabin, L. C., & Kim, J.
Affiliations
  • Indiana University Bloomington (US)
  • Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis Indiana USA
  • Indiana University Indianapolis (US)
Corresponding author
  • Dabin, Luke Child
  • Kim, Jungsu
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2026-08
Volume
22
Issue
8
Pages
e71742-e71742
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.71742
PMC
PMC13457352
OpenAlex
W7202208736
Semantic Scholar
e7e7431d87507eed959fd88f490842a811f5cb82
Cited by
0
References
41
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
National Institutes of Health (R01NS086794, R01AG077829, RF1AG074543, U01AG076804)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Mice, Transgenic, Neuroglia, Oligodendroglia, Microglia, Lipid Metabolism, Mice, Transcriptome

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.

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