CoChat
Sign Up
Cited by 42Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease

Open access
Huang, Yong, Wang, Minghui, Ni, Haofei, Zhang, Jinglong, Li, Aiqun, Hu, Bin, Junqueira Alves, Chrystian, Wahane, Shalaka +12 more·2024·Nature Neuroscience
DOI 10.1038/s41593-024-01664-wPMC PMC11346591

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Communication between glial cells has a profound impact on the pathophysiology of Alzheimer’s disease (AD). We reveal here that reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to amyloid deposits. This process is governed by guidance receptor Plexin-B1 (PLXNB1), a network hub gene in individuals with late-onset AD that is upregulated in plaque-associated astrocytes. Plexin-B1 deletion in a mouse AD model led to reduced number of reactive astrocytes and microglia in peri-plaque glial nets, but higher coverage of plaques by glial processes, along with transcriptional changes signifying reduced neuroinflammation. Additionally, a reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy. Altogether, our study demonstrates that Plexin-B1 regulates peri-plaque glial net activation in AD. Relaxing glial spacing by targeting guidance receptors may present an alternative strategy to increase plaque compaction and reduce neuroinflammation in AD. The axon guidance receptor Plexin-B1 regulates the cellular interaction of peri-plaque astrocytes with microglia to affect the pathophysiology of Alzheimer’s disease.

AI snapshot

Written from the paper’s full text.

TL;DR

Plexin-B1 is identified as a late-onset AD network hub that is upregulated in peri-plaque reactive astrocytes and enforces cell distancing in peri-plaque glial nets. Deleting Plexin-B1 in APP/PS1 mice compacts glial nets, increases glial coverage of amyloid, reduces plaque burden and neuritic dystrophy, shifts plaques toward dense-core type, and improves working memory.

Key findings

  • PLXNB1 was a hub gene in a late-onset AD subnetwork enriched for astrocyte-specific genes (3.6-fold) and AD-upregulated genes (2.9-fold), with enrichment for “Regulation of small GTPase mediated signal transduction” (6.5-fold); PLXNB1 expression positively correlated with amyloid plaque density in superior temporal gyrus and parahippocampal gyrus and was particularly upregulated in AD subtypes C1 and C2.
  • Plexin-B1 was predominantly upregulated in peri-plaque GFAP+ reactive astrocytes in APP/PS1 mice and in corona-like patterns around human AD plaques; peri-plaque Plexin-B1 scores positively correlated with “ABC” neuropathology scores in 11 AD patient specimens, including 3 with no clinical AD symptoms.
  • APP/PS1 PB1-KO mice had smaller peri-plaque glial nets with >50% fewer reactive astrocytes, reduced astrocyte and microglia spacing, and higher glial coverage of amyloid plaques; scRNA-seq of 27,286 cells showed DAA-like astrocyte sc-8 with 514 upregulated and 699 downregulated DEGs, and DAM-like microglia sc-9 expanded from 1% in WT to 4% in APP/PS1 but reduced to 2% in APP/PS1 PB1-KO, with 1,075 DEGs (1,070 up, 5 down).
  • PB1-KO reduced plaque burden and average plaque size by almost 50%, reversed plaque composition from ~50% fibrillar/35% mixed/15% dense-core in APP/PS1 to 15% fibrillar/35% mixed/50% dense-core, reduced LAMP1-labeled areas by 50%, and improved working memory acquisition in Barnes maze while probe-trial recall was similar.

Methods

  • Multiscale gene network analysis used MSBB AD cohort transcriptomic/genomic data, including a Bayesian network from parahippocampal gyrus RNA-seq of 215 subjects; human snRNA-seq datasets were reanalyzed with Seurat/MAST, and gene ontology enrichment used Enrichr.
  • Mouse studies used APP/PS1 and Plxnb1 knockout lines on C57BL/6J background; readouts included RNAscope ISH, immunofluorescence, IHC, X-Gal/Congo red, bulk RNA-seq, scRNA-seq (27,286 cells from WT, PB1-KO, APP/PS1, APP/PS1 PB1-KO), primary astrocyte/microglia cultures, cytokine/ApoE ELISAs, hanging-drop aggregation, and Barnes maze.
  • Human validation included IHC on postmortem AD brain specimens (11 patients, 3 without clinical AD symptoms) and CRISPR/Cas9 PLXNB1 knockout in two isogenic hiPSC pairs differentiated into astrocytes and co-cultured with human microglia; cell-cell communication was analyzed with CellphoneDB.

Limitations

  • The paper states that the molecular identity and cellular source of activating signals for Plexin-B1 in AD brains require further studies; it cannot exclude effects from low Plexin-B1 expression in microglia; human RNAscope/IF for Plexin-B1 yielded high background likely due to postmortem tissue preservation; and neurons were underrepresented in scRNA-seq due to single-cell dissociation.
  • Evident from the text: scRNA-seq was performed with one mouse per genotype condition, limiting biological replication; the human IHC cohort was small (11 patients) and used a 0–3 peri-plaque Plexin-B1 scoring scale; and the main functional evidence comes from an amyloidogenic APP/PS1 mouse model rather than human causal perturbation.

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

Integrity signals

Registry

Crossref · 10.1038/s41593-024-01664-w

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

47 of 58 cited sources checked · 29 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    Plexin-B1 (PLXNB1) is a hub gene in a coregulated gene subnetwork underlying late-onset AD.

    “This identified Plexin-B1 (gene symbol PLXNB1), an axon guidance receptor, as a hub in a coregulated gene subnetwork underlying late-onset AD (Fig. 1A).”
    • Also stated in: § INTRODUCTION · plain
      “our recent multi-omics analysis of a Mount Sinai Brain Bank AD patient cohort12, 13 has identified Plexin-B1 (gene symbol PLXNB1) as a hub gene in a subnetwork underlying late-onset AD”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Wang, M. et al. Transformative network modeling of multi-omics data reveals detailed circuits, key regulators, and potential therapeutics for Alzheimer’s disease. Neuron 109, 257–272 (2021). source

      The Results section, “Networks of LOAD brains highlight multiple neuronal modules” (page not available), describes coexpression subnetworks in late-onset Alzheimer’s disease. The Results section on Bayesian network analysis names other key drivers, but searches for “PLXNB1,” “Plexin,” and “Plexin-B1” found no passage identifying PLXNB1 as a hub. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [13] Wang, M. et al. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci. Data 5, 180185 (2018). source

      The Usage Notes, under “Use case 3: Gene and protein integrative network analysis,” discuss how network analysis can identify hub regulators in AD, but do not identify Plexin-B1 as one. Searches for PLXNB1, Plexin-B1, and an axon-guidance hub found no passage in our copy establishing the specific claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The presence of Plxnb1 mRNA puncta in hypertrophic processes of reactive astrocytes signifies local translation.

    “signifying local translation, a scenario described for Gfap and other key astrocyte genes35, 36.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [35] Sakers, K. et al. Astrocytes locally translate transcripts in their peripheral processes. Proc. Natl Acad. Sci. USA 114, E3830–E3838 (2017). source

      The Discussion and Fig. 2 report local protein synthesis in peripheral astrocyte processes, and Fig. 5 includes Gfap among the mRNAs examined for localization. The paper does not study Plxnb1 or reactive, hypertrophic astrocytes; it also does not establish that mRNA puncta alone signify translation of a particular transcript. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [36] Boulay, A. C. et al. Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface. Cell Discov. 3, 17005 (2017). source
  • Premisecitation

    PLXNB1 was identified as a key node in a gene module highly associated with cognitive decline in AD patients of the ROS-MAP cohort.

    “PLXNB1 was identified as a key node in a gene module highly associated with cognitive decline in AD patients of the ROS-MAP cohort26.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Mostafavi, S. et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease. Nat. Neurosci. 21, 811–819 (2018). source

      The Results sections on module 109 identify PLXNB1 as a major hub in a module strongly associated with cognitive decline in ROSMAP. But the Data origin and phenotypes section says the analysis included participants with and without AD dementia, so describing the finding as specifically being in “AD patients” narrows the study population inaccurately. Page numbers were not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingcitation

    PLXNB1 is specifically upregulated in astrocytes but not other cell types in human AD brains.

    “We next analyzed recent snRNA-seq datasets of AD patients from two independent studies28, 33, both showing a specific upregulation of PLXNB1 in astrocytes but not other cell types in human AD brains (Fig. 2B).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [28] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source

      The systematic differential-expression analysis and Discussion report cell-type-specific changes in human AD tissue, including astrocytes, but do not identify PLXNB1. Searches for “PLXNB1” and “plexin B1 astrocytes AD pathology upregulated” found no passage establishing its upregulation in astrocytes or its absence in other cell types. The indexed passages have section labels but no page numbers. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [33] Zhou, Y. et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26, 131–142 (2020). source

      The Results section on human AD astrocytes reports elevated NCAN and COL5A3 expression, but does not address PLXNB1. Searches for “PLXNB1” and “plexin B1” found no passage establishing its upregulation in astrocytes or its absence in other cell types. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Findingcitation

    Plexin-B1 is predominantly expressed in astrocytes as compared to other cell types in both mouse and human CNS.

    “a survey of gene expression databases (brainrnaseq.org)31, 32 revealed a predominant expression of Plexin-B1 in astrocytes as compared to other cell types in both mouse and human CNS (Fig. 2A).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [31] Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016). source
    • cites [32] Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014). source

      The Introduction describes a searchable RNA-sequencing database comparing astrocytes with other cell types from mouse cerebral cortex, so the citation supports the use of that database for the mouse comparison. Although Plxnb1 appears in the Additional information, our copy does not establish the claimed astrocyte predominance for that gene, and the study describes mouse—not human—cell data. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 32
  • May combine two claims. 42

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

    Premisecitation

    Cognitive decline and memory loss from neurodegeneration are linked to deposition of extracellular amyloid β (Aβ) and intracellular accumulation of neurofibrillary tangles of phospho-tau.

    “Cognitive decline and memory loss from neurodegeneration are linked to deposition of extracellular amyloid β (Aβ) and intracellular accumulation of neurofibrillary tangles of phospho-tau2.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Gandy, S. & DeKosky, S. T. Toward the treatment and prevention of Alzheimer’s disease: rational strategies and recent progress. Annu. Rev. Med 64, 367–383 (2013). source

      The treatment-trials section links amyloidosis and tau pathology to Alzheimer’s disease and says tau pathology correlates with cognition. The biomarker-diagnosis section identifies amyloid plaques and neurofibrillary tangles as AD pathology. Our copy does not specify that the deposits are extracellular or the tangles intracellular and composed of phosphorylated tau. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Amyloid plaques represent a pathological hallmark of AD.

    “Amyloid plaques represent a pathological hallmark of AD3”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Gandy, S. & Ehrlich, M. E. Alzheimer mutant speeds APP transport. J. Exp. Med. 218, e20210511 (2021). source

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

    Premisecitation

    Microglial coverage of amyloid plaques serves as a barrier to reduce exposure of neurotoxic protofibrillar Aβ hotspots to neurites.

    “Microglial coverage of amyloid plaques also serves as a barrier to reduce exposure of neurotoxic protofibrillar Aβ hotspots to neurites7.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015). source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    All mouse cohorts were bred onto C57BL/6J genetic background to ensure phenotypic consistency of amyloid deposition.

    “To ensure phenotypic consistency of amyloid deposition8, all mouse cohorts were bred onto C57BL/6J genetic background.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Smit, T. et al. Reactive astrocytes as treatment targets in Alzheimer’s disease-Systematic review of studies using the APPswePS1dE9 mouse model. Glia 69, 1852–1881 (2021). source

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

    Premisecitation

    Plexin-B1 has important roles in immune system activation and bone homeostasis in adult physiology.

    “However Plexin-B1 has importance roles in immune system activation and bone homeostasis in adult physiology23–25”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [23] Okuno, T. et al. Roles of Sema4D-Plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol. 184, 1499–1506 (2010). source
    • cites [24] Takamatsu, H. et al. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat. Immunol. 11, 594–600 (2010). source

      The Results section identifies plexin-A1, not plexin-B1, as important for dendritic-cell trafficking and antigen-specific T-cell responses. The References list a separate work on plexin-A1 and bone homeostasis. Searches for plexin-B1 and bone homeostasis found no passage addressing the claimed roles of plexin-B1; findings about A1 do not establish or rule out roles for B1. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [25] Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med. 17, 1473–1480 (2011). source

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

    Premisecitation

    Plexins and their cognate semaphorin ligands mediate a variety of cell-cell communications in development, adult physiology, and cancer.

    “In addition to axon pathfinding during neurodevelopment, plexins and their cognate semaphorin ligands also mediate a variety of cell-cell communications in development, adult physiology, and cancer15–18.”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [15] Jongbloets, B. C. & Pasterkamp, R. J. Semaphorin signalling during development. Development 141, 3292–3297 (2014). source
    • cites [16] Koropouli, E. & Kolodkin, A. L. Semaphorins and the dynamic regulation of synapse assembly, refinement, and function. Curr. Opin. Neurobiol. 27, 1–7 (2014). source

      The Introduction section on pathway-specific connectivity describes Sema3E–PlexinD1 signaling between neurons during CNS circuit development, supporting the developmental cell-communication part of the claim. The passages in our copy do not establish the attributed roles in adult physiology or cancer. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [17] Gurrapu, S. & Tamagnone, L. Transmembrane semaphorins: multimodal signaling cues in development and cancer. Cell Adh. Migr. 10, 675–691 (2016). source
    • cites [18] Hota, P. K. & Buck, M. Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell. Mol. Life Sci. 69, 3765–3805 (2012). source

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

    Premisecitation

    Plexins have a highly conserved domain structure, particularly the ring-shaped extracellular domain and intracellular Ras-GAP domain.

    “Our recent evolutionary studies revealed a highly conserved domain structure of plexins, particularly the ring-shaped extracellular domain and intracellular Ras-GAP domain19, 20”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [19] Junqueira Alves, C. et al. Evolution and diversity of semaphorins and plexins in choanoflagellates. Genome Biol. Evol. 13, evab035 (2021). source
    • cites [20] Junqueira Alves, C., Yotoko, K., Zou, H. & Friedel, R. H. Origin and evolution of plexins, semaphorins, and Met receptor tyrosine kinases. Sci. Rep. 9, 1970 (2019). source

  • May combine two claims.

    Premisecitation

    In AD brains, amyloid plaques are surrounded by activated microglia and reactive astrocytes that upregulate GFAP and extend hypertrophic arborized processes.

    “In AD brains, amyloid plaques are surrounded not only by activated microglia but also by reactive astrocytes that respond to pathological stimuli by upregulating GFAP and extending hypertrophic arborized processes8.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Smit, T. et al. Reactive astrocytes as treatment targets in Alzheimer’s disease-Systematic review of studies using the APPswePS1dE9 mouse model. Glia 69, 1852–1881 (2021). source

      The Introduction (page unavailable) says amyloid plaques are surrounded by activated microglia and reactive astrocytes, and describes GFAP upregulation and cellular hypertrophy in reactive astrocytes. It does not establish the more specific description that plaque-associated astrocytes extend hypertrophic, arborized processes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Glial communication is essential for brain homeostasis and injury responses.

    “Glial communication is essential for brain homeostasis and injury responses4.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Matejuk, A. & Ransohoff, R. M. Crosstalk between astrocytes and microglia: an overview. Front. Immunol. 11, 1416 (2020). source

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

    Premisecitation

    Microglia-derived factors (e.g., IL-1α, TNF, and C1q) can induce astrocytes into an inflammatory phenotype.

    “While it has been shown that microglia-derived factors (e.g., IL-1α, TNF, and C1q) can induce astrocytes into an inflammatory phenotype10”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source

  • May combine two claims.

    Premisecitation

    Reactive astrocytes and microglia closely interact with one another and with Aβ, forming peri-plaque glial nets.

    “Reactive astrocytes and microglia closely interact with one another and with Aβ, forming peri-plaque glial nets9.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Bouvier, D. S. et al. High resolution dissection of reactive glial nets in Alzheimer’s disease. Sci. Rep. 6, 24544 (2016). source

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

    Premisecitation

    Plexin-B1 knockout mice are viable and fertile, with no overt neurodevelopmental defects.

    “Plexin-B1 knockout (KO) mice are viable and fertile, with no overt neurodevelopmental defects21, 22.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [21] Deng, S. et al. Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo. J. Neurosci. 27, 6333–6347 (2007). source
    • cites [22] Fazzari, P. et al. Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev. Biol. 7, 55 (2007). source

  • May combine two claims.

    Premisecitation

    Plexin-B1 protein levels positively correlate with amyloid plaque load and tau neurofibrillary tangle density in AD patients.

    “Proteomics studies revealed a positive correlation of Plexin-B1 protein levels with amyloid plaque load and tau neurofibrillary tangle density in AD patients27.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Yu, L. et al. Targeted brain proteomics uncover multiple pathways to Alzheimer’s dementia. Ann. Neurol. 84, 78–88 (2018). source

      The Results section (“PLXNB1 and β-amyloid pathology”; page not provided) reports that higher PLXNB1 protein abundance was associated with greater β-amyloid load and more PHFtau tangles. However, “Characteristics of study participants” says only 41.9% had Alzheimer’s dementia, so the reported association was not specifically established in AD patients. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Amyloid plaques are typically surrounded by a halo of dystrophic neuronal membranes.

    “Amyloid plaques are typically surrounded by a halo of dystrophic neuronal membranes7.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015). source

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

    Premisecitation

    Dense-core plaques correspond to reduced neurotoxicity due to limited dissemination of neurotoxic soluble Aβ oligomers.

    “The reduced neuritic dystrophy observed in APP/PS1 PB1-KO mice aligned with the model that dense-core plaques correspond to reduced neurotoxicity due to limited dissemination of neurotoxic soluble Aβ oligomers52.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Huang, Y. et al. Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat. Immunol. 22, 586–594 (2021). source

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

    Study design and conductcitation

    Neurons were underrepresented in the scRNA-seq analysis due to technical factors related to single cell dissociation.

    “Due to technical factors related to single cell dissociation41, neurons were underrepresented in this analysis.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Bakken, T. E. et al. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types. PLoS ONE 13, e0209648 (2018). source

  • May combine two claims.

    Findingown data

    Sc-8 astrocytes displayed an enrichment for gene signatures of Disease-associated astrocytes (DAA), reactive astrocytes linked to inflammatory state, and EAE astrocytes.

    “Moreover, sc-8 astrocytes displayed an enrichment for gene signatures of Disease-associated astrocytes (DAA) identified in an AD mouse model42, reactive astrocytes linked to inflammatory state10, as well as EAE astrocytes43 (Fig. 4G).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [42] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). source
    • cites [10] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source
    • cites [43] Burda, J. E. et al. Divergent transcriptional regulation of astrocyte reactivity across disorders. Nature 606, 557–564 (2022). source

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

    Premisecitation

    Elevated IGFBP levels have been associated with more severe outcomes in AD patients by inhibiting the neuroprotective effects of IGF proteins.

    “Of note, elevated IGFBP levels have been associated with more severe outcomes in AD patients by inhibiting the neuroprotective effects of IGF proteins50.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] McGrath, E. R. et al. Circulating IGFBP-2: a novel biomarker for incident dementia. Ann. Clin. Transl. Neurol. 6, 1659–1670 (2019). source

      The Background (page not provided) says elevated IGF-binding proteins are thought to inhibit the neuroprotective effects of IGFs and reports an association between IGFBP-2 and AD. The Results (page not provided) link elevated IGFBP-2 to the risk of developing AD dementia, not to more severe outcomes among patients who already have AD; the proposed mechanism is also presented as a hypothesis, not an established cause. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A prerequisite to detect and engulf Aβ amyloid material is an adequate coverage of the amyloid plaque by glial processes, which involves morphological transformation of astrocytes and microglia upon contact with Aβ amyloid.

    “A prerequisite to detect and engulf Aβ amyloid material is an adequate coverage of the amyloid plaque by glial processes, which involves morphological transformation of astrocytes and microglia upon contact with Aβ amyloid52.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] Huang, Y. et al. Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat. Immunol. 22, 586–594 (2021). source

      The Results (‘Microglial TAM activity at plaques’; page unavailable) describe changes in microglial morphology and plaque-directed processes, while the Discussion links microglial plaque attachment and process responses to engulfment. The paper does not establish adequate coverage by glial processes as a prerequisite for detection and engulfment, or show that astrocytes undergo the claimed morphological transformation upon plaque contact. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent studies have unveiled a role of Plexins in cell collision guidance.

    “Plexin signaling is best known for growth cone collapse during neurodevelopment; recent studies from our laboratory and others have further unveiled a role of Plexins in cell collision guidance58, 59.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [58] Deb Roy, A. et al. Optogenetic activation of Plexin-B1 reveals contact repulsion between osteoclasts and osteoblasts. Nat. Commun. 8, 15831 (2017). source
    • cites [59] Zhou, X. et al. Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2. Nat. Neurosci. 23, 337–350 (2020). source

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

    Premisecitation

    A nanobody blocking Plexin-B1 has recently been developed.

    “In this context it is noteworthy that while small molecule inhibitors of plexin signaling are currently unavailable, a function-blocking antibody against Sema4D is being tested in a clinical trial for AD63, and a nanobody blocking Plexin-B1 has recently been developed64.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [64] Cowan, R. et al. Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signaling. J. Biol. Chem. 299, 104740 (2023). source

  • May combine two claims.

    Interpretationcitation

    In the absence of Plexin-B1, relaxed cell distancing may physically permit closer access of microglia to plaques, which in turn elicits morphological and transcriptomic transformation of microglia to a DAM state.

    “Moreover, in absence of Plexin-B1, relaxed cell distancing may physically permit closer access of microglia to plaques, which in turn elicits morphological and transcriptomic transformation of microglia to a DAM state44.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [44] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      The Results report DAM-marker-positive microglia near Aβ plaques and a transcriptional transition from homeostatic microglia to DAM. They do not establish that closer plaque access elicits that transition or a morphological transformation; the paper also does not address Plexin-B1 or relaxed cell distancing. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A recent study in a mouse model of multiple sclerosis showed that Sema4D expressed by microglia can activate Plexin-B1 and -B2 expressed in astrocytes.

    “A recent study in a mouse model of multiple sclerosis (MS) showed that Sema4D expressed by microglia can activate Plexin-B1 and -B2 expressed in astrocytes61.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] Clark, I. C. et al. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science 372, eabf1230 (2021). source

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

    Premisecitation

    A recent study reported a semaphorin-independent mechanosensitive function for Plexin-D1, a paralog of Plexin-B1, to detect blood flow shear stress in endothelial cells.

    “Interestingly, a recent study also reported a semaphorin-independent mechanosensitive function for Plexin-D1, a paralog of Plexin-B1, to detect blood flow shear stress in endothelial cells62.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Mehta, V. et al. The guidance receptor plexin D1 is a mechanosensor in endothelial cells. Nature 578, 290–295 (2020). source

      The main text (page unavailable) reports that PlxnD1 is a direct force sensor in endothelial cells and is required for their response to blood-flow shear stress. It also states that this mechanotransduction is independent of the semaphorin ligand Sema3E. Our copy does not identify PlxnD1 as a paralog of Plexin-B1, so that parenthetical part is not supported by this source. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Contact inhibition of locomotion has been reported for Plexin-B1 mediated physical contact between osteoclasts and osteoblasts.

    “This process, termed contact inhibition of locomotion (CIL), has also been reported for Plexin-B1 mediated physical contact between osteoclasts and osteoblasts58.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [58] Deb Roy, A. et al. Optogenetic activation of Plexin-B1 reveals contact repulsion between osteoclasts and osteoblasts. Nat. Commun. 8, 15831 (2017). source

  • May combine two claims.

    Findingown data

    Astrocytic processes display polarization towards amyloid plaques in PB1-KO, with increased contact with amyloid material and higher plaque coverage.

    “astrocytic processes displayed polarization towards amyloid plaques in PB1-KO, with increased contact with amyloid material and higher plaque coverage (Fig. 3B, C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PLXNB1 is particularly upregulated in C1 and C2 AD subtypes with enrichment of Aβ-associated gene changes.

    “We found that PLXNB1 was particularly upregulated in C1 and C2, two AD subtypes with enrichment of Aβ-associated gene changes (Fig. 1D, E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spacing or cell-cell distancing of plaque-associated astrocytes is reduced in APP/PS1 PB1-KO mice, with GFAP+ cells crowding in smaller glial nets.

    “spacing or cell-cell distancing of plaque-associated astrocytes appeared reduced in APP/PS1 PB1-KO mice, with GFAP+ cells crowding in smaller glial nets (Fig. 3B, C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In matching cortical areas of APP/PS1 PB1-KO mice, peri-plaque glial nets had a much smaller footprint, with reduced number of reactive astrocytes (over 50%), extending only about one-cell layer deep.

    “in matching cortical areas of APP/PS1 PB1-KO mice of the same age and same C57BL/6J genetic background, we observed a much smaller footprint of peri-plaque glial nets, with reduced number of reactive astrocytes (over 50%), extending only about one-cell layer deep (Fig. 3A–C; Fig. S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The PLXNB1-centered gene network is significantly enriched for astrocyte-specific genes (3.6-fold enrichment) and AD upregulated genes (2.9-fold enrichment).

    “The PLXNB1-centered gene network was significantly enriched for astrocyte-specific genes (3.6-fold enrichment) and AD upregulated genes (2.9-fold enrichment) (Fig. 1B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spacing of plaque-associated microglia is reduced with PB1-KO, resulting in increased microglial density in glial nets and higher microglial coverage of amyloid plaque material.

    “As with reactive astrocytes, the spacing of plaque-associated microglia was also reduced with PB1-KO, resulting in increased microglial density in glial nets and higher microglial coverage of amyloid plaque material (Fig. 3B, D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upregulated genes in sc-9 microglia featured microglial cell activation, chemoattraction, and host defense response.

    “Pathway enrichment analysis showed that the upregulated genes in sc-9 microglia featured microglial cell activation (Cx3cr1, C1qa, Grn, Ifngra, Aif1 (encoding Iba1), Tnf), chemoattraction (Cx3cr1, Ccrl2, Ccr5), and host defense response (Ubb, B2m, Tlr2) (Fig. 5F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Phalloidin staining revealed reduced F-actin and diminished astrocytic processes of Plxnb1−/− astrocytes.

    “Phalloidin staining also revealed reduced F-actin and diminished astrocytic processes of Plxnb1−/− astrocytes (Fig. 6A)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The amyloidogenic APP/PS1 transgene resulted in expansion of sc-9 microglia from 1% in WT to 4% in APP/PS1, and sc-9 was reduced to 2% in APP/PS1 PB1-KO.

    “Specifically, while the amyloidogenic APP/PS1 transgene resulted in a substantial expansion of sc-9 microglia from 1% in WT to 4% in APP/PS1, the subcluster sc-9 was reduced to 2% in APP/PS1 PB1-KO.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plexin-B1 KO affected signaling communications from microglia to astrocytes in APP/PS1 condition, with the majority showing enhanced signaling, including cell adhesion, chemoattraction/repulsion, lipid metabolism, and phagocytosis; only Sema4D⇾Plexin-B1 and IGF1 signaling were attenuated.

    “Conversely, Plexin-B1 KO also affected signaling communications from microglia to astrocytes in APP/PS1 condition, again with majority showing enhanced signaling (Fig. S6A). This included ligand-receptor pairs concerning cell adhesion (CADM1⇾CADM1), chemoattraction/repulsion (EFNB1⇾EPHB3, CSF1⇾CSF1R), lipid metabolism (ApoE⇾TREM2, LDL receptor⇾Sortilin1, and phagocytosis (GAS6⇾AXL). Only two pairs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expression levels of Axl and Trem2 appeared comparable in both cohorts, but the spatial patterns appeared more compact in PB1-KO.

    “The expression levels of Axl and Trem2 appeared comparable in both cohorts, but the spatial patterns appeared more compact in PB1-KO, consistent with reduced footprint of glial cells (Fig. S6C–D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In control co-cultures, astrocytes extended long and slender processes, while microglia formed distinct clusters.

    “In control co-cultures, astrocytes extended long and slender processes, while microglia formed distinct clusters (Fig. 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PB1-KO resulted in an overall augmentation of signaling communication from reactive astrocytes to microglia, featuring neuroprotection, chemoattraction, cell adhesion, and lipid metabolism; only the Sema4D⇾CD45 pair was reduced.

    “Results showed that PB1-KO resulted in an overall augmentation of signaling communication from reactive astrocytes to microglia (Fig. S6A), featuring neuroprotection (Prosapin⇾GRP3), chemoattraction (Chemerin⇾CCRL2), cell adhesion (JAM3⇾Integrin aMb2), and lipid metabolism (APOA1⇾ABCA1, APOA1⇾TREM2). Only one ligand-receptor signaling pair was reduced by PB1-KO, involving Plexin ligand Sema4D (i.e”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the cortex of APP/PS1 mice, close to 50% plaques were fibrillar type, 35% mixed, and 15% dense-core.

    “We found that in the cortex of APP/PS1 mice, close to 50% plaques were fibrillar type, 35% mixed, and 15% dense-core; by contrast, in APP/PS1 PB1-KO mice the composition was reversed (15% fibrillar, 35% mixed, and 50% dense-core type) (Fig. 7D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plxnb1 was predominantly expressed in the astrocyte cluster, and expression was efficiently ablated in PB1-KO condition.

    “We first confirmed in our scRNA-seq data that Plxnb1 was predominantly expressed in the astrocyte cluster, and that expression was efficiently ablated in PB1-KO condition (Fig. 4B, C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sc-8 astrocytes showed the strongest association with reactive astrocytes, expressing high levels of Gfap and Vim, while Aqp4 was ubiquitously expressed in all subclusters.

    “Sc-8 astrocytes showed the strongest association with reactive astrocytes, expressing high levels of Gfap and Vim (vimentin), both intermediate filament genes highly upregulated in reactive astrocytes, while Aqp4 (aquaporin-4) was ubiquitously expressed in all subclusters (Fig. 4E).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Among 10 distinct cell type clusters defined by marker gene expression, microglia formed the largest cluster (43%), followed by endothelial cells (22.6%) and astrocytes (16.6%).

    “Among the 10 distinct cell type clusters defined by marker gene expression, microglia formed the largest cluster (43%), followed by endothelial cells (22.6%), astrocytes (16.6%), and other cell types with smaller shares”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is a significant reduction of both the size and number of ATG9A-labeled areas near plaques.

    “This revealed a significant reduction of both the size and number of ATG9A-labeled areas near plaques (Fig. 8A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Downregulated DEGs in PB1-KO concerned tissue inflammation and tissue damage, detection of mechanical stimuli, and protein deacetylase activity.

    “The downregulated DEGs in PB1-KO concerned tissue inflammation and tissue damage (e.g., TNF-activated receptor activity, CD95 death-induced signaling complex, phagolysosome, collagen fibril organization), detection of mechanical stimuli, and protein deacetylase activity (Fig. S4C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Primary cell culture studies illustrated a central function of Plexin-B1 in controlling cell spacing of astrocytes, as well as cytokine expression profiles and microglia clustering.

    “In support, our primary cell culture studies illustrated a central function of Plexin-B1 in controlling cell spacing of astrocytes, as well as cytokine expression profiles and microglia clustering.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plexin-B1 deletion led to transcriptional changes linked to enhanced activation profiles of disease-associated astrocytes and microglia, as well as augmented ligand-receptor signaling communication, featuring chemoattraction, ECM remodeling, and lipid metabolism.

    “In support of improved efficiency of glial cells to clear Aβ deposits, our scRNA-seq data revealed that Plexin-B1 deletion led to transcriptional changes linked to enhanced activation profiles of disease-associated astrocytes and microglia, as well as augmented ligand-receptor signaling communication, featuring chemoattraction, ECM remodeling, and lipid metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to Aβ.

    “Here, we reveal that reactive astrocytes play a role in controlling cell distancing in peri-plaque glial nets, which restricts microglial access to Aβ, a prerequisite to detect and engulf amyloid deposits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Plexin-B1 promotes cell distancing in peri-plaque glial nets, which limits glial coverage of amyloid aggregates, leading to more diffuse plaques and exacerbated neuroinflammation and neurotoxicity.

    “Together, our results unveil a role of Plexin-B1 in promoting cell distancing in peri-plaque glial nets, which limits glial coverage of amyloid aggregates, leading to more diffuse plaques and exacerbated neuroinflammation and neurotoxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Plexin-B1 governs the process of cell distancing in peri-plaque glial nets and the restriction of microglial access to Aβ.

    “This process is governed by axon guidance receptor Plexin-B1, a network hub gene that we have identified in late-onset AD, whose expression levels correlate with plaque burden and disease severity in AD patients.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Plexin-B1 is a member of the plexin axon guidance receptor family.

    “Plexin-B1 is a member of the plexin axon guidance receptor family14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Tran, T. S., Kolodkin, A. L. & Bharadwaj, R. Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol. 23, 263–292 (2007). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Microglia are important in engulfing and processing of Aβ.

    “Recent advances have unveiled the importance of microglia in engulfing and processing of Aβ5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Leng, F. & Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 17, 157–172 (2021). source

  • May combine two claims.

    Interpretationown data

    Transcriptomic and histological data converge on Plexin-B1 induction in peri-plaque reactive astrocytes, which correlates with amyloid plaque burden and disease severity in AD patients.

    “Altogether, transcriptomic and histological data converge on Plexin-B1 induction in peri-plaque reactive astrocytes, which correlates with amyloid plaque burden and disease severity in AD patients.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The phagocytic activity of microglia promotes plaque compaction, which limits the exposure of neighboring healthy neurons to Aβ material.

    “The phagocytic activity of microglia promotes plaque compaction, which limits the exposure of neighboring healthy neurons to Aβ material6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 92, 252–264 (2016). source

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

    Study design and conductreasoning

    Attempts of RNAscope ISH or IF staining for Plexin-B1 on human brain specimens yielded high background signals, likely due to preservation challenges for postmortem tissues.

    “Attempts of RNAscope ISH or IF staining for Plexin-B1 on human brain specimens yielded high background signals, likely due to preservation challenges for postmortem tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Plexin-B1 controls cell-cell distancing of astrocytes, resulting in wider spaced and looser peri-plaque glial nets; removing Plexin-B1 leads to smaller but more compact glial nets with higher density and increased plaque coverage by astrocytic processes.

    “These phenotypes illustrate a central role of Plexin-B1 in controlling cell-cell distancing of astrocytes, resulting in wider spaced and looser peri-plaque glial nets; removing Plexin-B1 led to smaller but more compact glial nets with higher density and increased plaque coverage by astrocytic processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tissue-level transcriptomics illustrate an overall protective effect of Plexin-B1 deletion, with improved neuronal/synaptic function and attenuated neuroinflammation/cell death.

    “Hence, tissue-level transcriptomics illustrate an overall protective effect of Plexin-B1 deletion, with improved neuronal/synaptic function and attenuated neuroinflammation/cell death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Plexin-B1 induction in peri-plaque areas governs glial cell mobilization and spacing, as well as glial access and coverage of amyloid, thereby impacting cytoarchitecture and footprint of glial nets in AD.

    “Together, these data illustrate that Plexin-B1 induction in peri-plaque areas governs glial cell mobilization and spacing, as well as glial access and coverage of amyloid, thereby impacting cytoarchitecture and footprint of glial nets in AD (Fig. 3E).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Plexin-B1 binds to class 4 semaphorins, a family with six ligands expressed in diverse cell types.

    “Plexin-B1 binds to class 4 semaphorins, a family with six ligands expressed in diverse cell types17, 60.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Gurrapu, S. & Tamagnone, L. Transmembrane semaphorins: multimodal signaling cues in development and cancer. Cell Adh. Migr. 10, 675–691 (2016). source
    • cites [60] Zhou, Y., Gunput, R. A. & Pasterkamp, R. J. Semaphorin signaling: progress made and promises ahead. Trends Biochem. Sci. 33, 161–170 (2008). source

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

    Study design and conductnone given

    The microglia preparation method yielded ~90% pure microglia with minimal neural cell contamination.

    “This method yielded ~90% pure microglia with minimal neural cell contamination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Reactive astrocytes, through Plexin-B1, regulate glial mobilization and enforce cell distancing in peri-plaque glial nets, leading to restricted glial coverage of Aβ deposits, more diffuse amyloid plaques, and increased neural tissue damage.

    “In summary, our data demonstrate a role of reactive astrocytes, through guidance receptor Plexin-B1, in regulating glial mobilization and enforcing cell distancing in peri-plaque glial nets, leading to restricted glial coverage of Aβ deposits, more diffuse amyloid plaques, and increased neural tissue damage.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mobilization of astrocytes and microglia in peri-plaque reactive glial nets is critical to clear Aβ, control neuroinflammation, and limit neurotoxicity.
    • Rests on an assumption: Insufficient access to amyloid deposits by glial processes results in poor Aβ clearance, more diffuse fibrillar plaques, and increased neurotoxicity, which may trigger a detrimental cycle of recruitment of more glial cells, heightened inflammation, and a larger footprint of reactive glial nets.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Successful gene editing was confirmed through Sanger sequencing of PCR products cloned into plasmids using TOPO cloning.

    “Successful gene editing was confirmed through Sanger sequencing of PCR products cloned into plasmids using TOPO cloning.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This may initiate a positive cycle of better Aβ clearance, a shift towards dense-core plaques, less neurotoxicity, reduced need for more glial mobilization, and overall smaller footprint of glial nets.

    “This may initiate a positive cycle of better Aβ clearance, a shift towards dense-core plaques, less neurotoxicity, thus a reduced need for more glial mobilization and thereby an overall smaller footprint of glial nets (Fig. 8C).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All animal procedures were conducted in accordance with protocols approved by the IACUC of Icahn School of Medicine at Mount Sinai.

    “All animal procedures were conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Icahn School of Medicine at Mount Sinai.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A function-blocking antibody against Sema4D is being tested in a clinical trial for AD.

    “In this context it is noteworthy that while small molecule inhibitors of plexin signaling are currently unavailable, a function-blocking antibody against Sema4D is being tested in a clinical trial for AD63, and a nanobody blocking Plexin-B1 has recently been developed64.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Evans, E. E. et al. Evidence that semaphorin 4D is upregulated in neurons in Huntington’s and Alzheimer’s diseases: effects of a SEMA4D blocking antibody on FDG-PET in a clinical trial, and treatment rationale for its use in AD. Alzheimers Dement. 16, e043971 (2020). source

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

    Study design and conductnone given

    All tissue samples were obtained de-identified under approved IRB protocols under consultation with the Ethics Committee of the Medical Board at the Mount Sinai Hospital.

    “All tissue samples were obtained de-identified under approved Institutional Review Board (IRB) protocols under consultation with the Ethics Committee of the Medical Board at the Mount Sinai Hospital.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Phagocytic microglia in PB1-KO were confined in smaller glial nets, with improved access to amyloid deposits.

    “Hence, the abundance of phagocytic microglia was not expanded in PB1-KO, but they were confined in smaller glial nets, with improved access to amyloid deposits.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All research involving hiPSCs was carried out under the supervision and approval of the Institutional Review Board (IRB) and the Embryonic Stem Cell Research Overview (ESCRO) committees at the Icahn School of Medicine at Mount Sinai.

    “All research involving hiPSCs was carried out under the supervision and approval of the Institutional Review Board (IRB) and the Embryonic Stem Cell Research Overview (ESCRO) committees at the Icahn School of Medicine at Mount Sinai.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Informed consent was obtained from all skin cell donors as part of a study directed by Judith Rapoport MD at the National Institute of Mental Health (NIMH).

    “Informed consent was obtained from all skin cell donors as part of a study directed by Judith Rapoport MD at the National Institute of Mental Health (NIMH).”
    Quote in the paperNot a substantial claim
68 of 68

  • The authors state this as an assumption.

    The governing factors of Aβ deposition, clearance, and plaque compaction are not fully understood.

    “but the governing factors of Aβ deposition, clearance, and plaque compaction are not fully understood.”

  • The authors state this as an assumption.

    The mechanisms governing microglial access and coverage of Aβ are not well-defined.

    “However, the mechanisms governing microglial access and coverage of Aβ, a prerequisite to detect and engulf amyloid material, are not well-defined.”

  • The authors state this as an assumption.

    The signaling pathways controlling the physical contacts of glial cells with one another and with amyloid plaques are less understood.

    “less is understood of the signaling pathways controlling the physical contacts of these glial cells with one another and with amyloid plaques.”

  • The authors state this as an assumption.

    The gene programs operating in plaque-associated astrocytes remain opaque.

    “however the gene programs operating in plaque-associated astrocytes remain opaque.”

  • The authors state this as an assumption.

    Plexin-B1's function in AD pathophysiology remains unclear.

    “but its function in AD pathophysiology remains unclear.”

  • The authors state this as an assumption.

    In vivo functional data for Plexin-B1 in AD are lacking.

    “While these omics data link Plexin-B1 to AD, in vivo functional data are lacking.”

  • The authors state this as an assumption.

    Plexin-B1's functions in CNS pathology remain largely unexplored.

    “and its functions in CNS pathology remain largely unexplored.”

  • The paper relies on this without support.

    Mobilization of astrocytes and microglia in peri-plaque reactive glial nets is critical to clear Aβ, control neuroinflammation, and limit neurotoxicity.

    “Mobilization of astrocytes and microglia in peri-plaque reactive glial nets is critical to clear Aβ, control neuroinflammation, and limit neurotoxicity.”

  • The paper relies on this without support.

    Insufficient access to amyloid deposits by glial processes results in poor Aβ clearance, more diffuse fibrillar plaques, and increased neurotoxicity, which may trigger a detrimental cycle of recruitment of more glial cells, heightened inflammation, and a larger footprint of reactive glial nets.

    “Insufficient access to amyloid deposits by glial processes results in poor Aβ clearance, more diffuse fibrillar plaques, and increased neurotoxicity, which may trigger a detrimental cycle of recruitment of more glial cells, heightened inflammation, and a larger footprint of reactive glial nets.”
9 of 9

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.

  • Three attenuated ligand-receptor pairs are listed as two

    Minor

    The text says only two pairs were attenuated, but it names Sema4D⇾Plexin-B1 and two separate IGF1 pairs-three pairs in total.

1 of 1

Cites

Flagged first, then by citations

2 of the 88 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Huang, Y., Wang, M., Ni, H., Zhang, J., Li, A., Hu, B., Junqueira Alves, C., Wahane, S., Rios de Anda, M., Ho, L., Li, Y., Kang, S., Neff, R., Kostic, A., Buxbaum, J. D., Crary, J. F., Brennand, K. J., Zhang, B., Zou, H., & Friedel, R. H.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Tongji University (CN)
  • Second Affiliated Hospital of Xi'an Jiaotong University (CN)
  • Yale University (US)
Corresponding author
  • Zhang, Bin
  • Zou, Hongyan
  • Friedel, Roland H.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2024-05-27
Volume
27
Issue
8
Pages
1489-1504
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-024-01664-w
PMC
PMC11346591
OpenAlex
W4399047418
Semantic Scholar
86458d4dc10902cee40cfbf6fd9d54d26aa2d882
Cited by
42
References
88
Citations by year
2026: 15 · 2025: 23 · 2024: 4
FWCI
9.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1AG057440, U01AG046170)
  • New York State Department of Health (SCIRB C39068GG)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, Plexin-B1, reactive astrocytes, microglia, amyloid plaques, neuroinflammation, guidance receptors, plaque burden, neuritic dystrophy, glial communication
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Female, Humans, Male, Mice, Transgenic, Nerve Tissue Proteins, Neuroglia, Receptors, Cell Surface, Amyloid beta-Peptides, Microglia, Mice, Knockout, Mice, Plaque, Amyloid

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 2026-10-18.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.

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