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Cited by 19Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

Open access
Ibanez, Kristen R., McFarland, Karen N., Phillips, Jennifer, Allen, Mariet, Lessard, Christian B., Zobel, Lillian, De La Cruz, Elsa Gonzalez, Shah, Shivani +9 more·2022·Alzheimer's Research & Therapy
DOI 10.1186/s13195-022-01044-1PMC PMC9327202

Published version of a preprint

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Abstract

Background: The S209F variant of Abelson Interactor Protein 3 ( ABI3 ) increases risk for Alzheimer’s disease (AD), but little is known about its function in relation to AD pathogenesis. Methods: Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD—amyloid β plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. Results: Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3 − /− mice and document that both Abi3 and its overlapping gene, Gngt2 , are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3 - Gngt 2 −/− mice revealed upregulation of Trem2 , Plcg2 , and Tyrobp , concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3 - Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3 - Gngt2 −/− mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. Conclusions: These data provide an important experimental framework for understanding the role of Abi3 - Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.

AI snapshot

Written from the paper’s full text.

TL;DR

Deletion of the Abi3 locus, which also disrupts the overlapping Gngt2 gene, produces early AD-like immune gliosis and has opposing effects on amyloid and tau pathology in mice. Loss of Abi3-Gngt2 reduces Aβ deposition in an age- and gene-dose-dependent manner but exacerbates tau phosphorylation and astrocytosis.

Key findings

  • Abi3 RNA is expressed in microglia and non-microglial cells in human AD and APP mouse brain; Abi3 increases with age/plaque burden in APP TgCRND8 mice and is upregulated in AD brains (p = 4.47E-03), while rTg4510 tau mice show increased Abi3 at 4.5 months but reduced levels by 6 months.
  • ABI3 and GNGT2 are tightly co-regulated in human AD cohorts (Mayo TCX ρ = 0.644; Mayo CER ρ = 0.556; ROSMAP ρ = 0.328; all p = 2.2e−16) and in mouse models (TgCRND8 ρ = 0.625, p = 7.31e−06; rTg4510 ρ = 0.554, p = 0.018); 24 of 26 additional mouse cohorts showed concordant regulation.
  • Abi3-Gngt2−/− mice show early reactive gliosis and AD-associated transcriptomic signatures, including upregulation of Trem2, Plcg2, and Tyrobp and induction of the PIG network even without Aβ (p < 0.01 vs WT and heterozygous).
  • In APP mice, Abi3-Gngt2 loss reduced Aβ in a gene-dose- and age-dependent manner: at 3 months, heterozygous (p < 0.05) and knockout (p < 0.01) mice had reduced plaques; at 6 months, knockout mice had reduced total plaque burden (p < 0.05) and cored plaques (p < 0.01), but effects diminished by 9 months. In AAV tau models, P301L/S320F tau in Abi3-Gngt2−/− mice increased ptau at 3 months (CP13 and MC1, p < 0.05) and 6 months (p < 0.001), with higher astrocytosis. The S209F ABI3 mutation impaired phosphorylation: WT ABI3 migrated as a double band, S209F did not, and mutating position 209 to alanine or aspartate restored phosphorylation.

Methods

  • Mouse models: Abi3+/− mice (Jax B6N(Cg)-Abi3tm1.1(KOMP)Vlcg/J) were crossed to TgCRND8 APP mice to generate WT, heterozygous, and knockout Abi3-Gngt2 genotypes with or without APP; neonatal AAV1 delivery of control, WT 0N/4R human tau, or pro-aggregant P301L/S320F 0N/4R human tau was used for tau studies. Human formalin-fixed, paraffin-embedded AD and control brain tissue came from the University of Florida Neuromedicine Human Brain and Tissue Bank.
  • Neuropathology and biochemistry: immunohistochemistry, ThioS staining, RNAscope in situ hybridization, ELISA for Aβ42/Aβ40, sequential tau extraction, and Western blotting were used. Bulk RNAseq of forebrain was analyzed with DESeq2, WGCNA, cell-type signatures, and GO/KEGG enrichment.
  • Human/mouse correlation analyses used AMP-AD RNAseq datasets after QC: ROSMAP n = 631, Mayo TCX n = 259, Mayo CER n = 246. In vitro ABI3 phosphorylation studies used HEK293T cells transfected with WT or mutant ABI3 constructs and lambda protein phosphatase assays.

Limitations

  • The paper states that the mouse locus deletion affects two overlapping genes, Abi3 and Gngt2, so effects cannot be attributed to Abi3 alone.
  • The paper states that gene deletion studies may miss subtle physiological insights when genes have complex disease-stage- or age-dependent outcomes, and that the inferred loss-of-function premise for the AD-associated S209F variant needs validation in models carrying that variant.
  • The paper states that effects on Aβ and tau were inferred using independent, stand-alone models, so how Abi3-Gngt2 loss affects combined Aβ and tau pathologies remains to be characterized. The text also notes that neuronal ABI3 RNA in situ findings require confirmation by protein detection methods.

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

Integrity signals

Registry

Crossref · 10.1186/s13195-022-01044-1

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

66 of 74 cited sources checked · 29 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Manipulation of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have opposing effects on amyloid and tau pathologies.

    “Indeed, manipulation of expression of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have all been shown to have opposing effects on amyloid and tau pathologies [49–51, 55–65].”
    Quote in the paperNot a substantial claim8 of 10 sources checked
    • cites [49] Sayed FA, et al. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A. 2018;115(40):10172–7. source

      The Results section reports that partial loss of TREM2 increased tau pathology in P301S mice, whereas complete loss did not. The Discussion compares inflammatory responses in amyloid and tau models, but does not show opposing effects on amyloid versus tau pathology. This paper also does not establish the claimed effects for the other listed genes and cytokines. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [50] Leyns CEG, et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017;114(43):11524–9. source

      The Discussion (page unavailable) describes opposing consequences of TREM2 deficiency: greater amyloid-dependent toxicity but less neurodegeneration in the tauopathy model. It also says tau deposition was not detectably changed in that model, so the contrast is not an opposing effect on amyloid and tau pathology themselves. The paper does not establish the claimed opposing effects for Tyrobp, Cx3cl1/Cx3cr1, IL-1β, or IFN-γ; its Results report reduced IL-1β expression after TREM2 deficiency, not manipulation of IL-1β. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [51] Lee SH, et al. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology. Neuron. 2021;109(8):1283-1301 e6. source
    • cites [55] Audrain M, et al. Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau. Mol Psychiatry. 2019;24(9):1383–97. source

      The Discussion (page unavailable) reports that TYROBP deficiency increases tau phosphorylation and spread, while the Introduction (page unavailable) describes reduced microglial clustering around amyloid plaques in earlier TYROBP studies. These passages support effects on both processes, but do not establish opposing effects on amyloid and tau pathologies. This source also does not substantiate the listed Cx3cl1/Cx3cr1, IL1β, or IFN-γ manipulations; the sentence cites other papers as well. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [56] Haure-Mirande JV, et al. Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Abeta amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Abeta burden. Mol Psychiatry. 2019;24(3):431–46. source

      The Results report that Tyrobp deletion did not change amyloid-plaque burden in APP/PSEN1 mice, while the Discussion reports increased tau spread and phosphorylation after Tyrobp deletion in a tauopathy mouse model. This supports differing outcomes for Tyrobp, though not opposing changes in amyloid and tau burden. The paper does not establish the claimed amyloid-versus-tau effects for Trem2, Cx3cl1/Cx3cr1, IL1β, or IFN-γ. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [57] Meilandt WJ, et al. Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the Abeta42:Abeta40 Ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer’s mouse model. J Neurosci. 2020;40(9):1956–74. source
    • cites [58] Parhizkar S, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019;22(2):191–204. source

      The Results section (‘Increased amyloid plaque seeding in the absence of functional Trem2’; page unavailable) reports increased amyloidogenesis when Trem2 function is lost. The paper does not establish an opposing effect on tau pathology or effects of manipulating Tyrobp, Cx3cl1/Cx3cr1, IL1β, or IFN-γ, so it supports only the Trem2–amyloid portion of the attributed claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [59] Jay TR, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med. 2015;212(3):287–95. source

      The Results and Discussion sections on Aβ deposition and MAPT pathology report that TREM2 deficiency reduced both hippocampal amyloid deposition and plaque-associated phosphorylated MAPT in APPPS1 mice. For Trem2—the manipulation this source examines—the effects on amyloid and tau pathology were therefore in the same direction, not opposing directions. No page numbers are available in our copy. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [60] Chakrabarty P, et al. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J Immunol. 2010;184(9):5333–43. source

      The Results report that IFN-γ overexpression reduced amyloid plaque burden in APP transgenic mice. The Discussion reports decreased tau pathology in a different IFN-γ mouse study, but says that study did not report plaque burden and cautions against drawing parallels. This paper therefore supports an effect of IFN-γ on amyloid pathology, not the claimed opposing effects on amyloid and tau pathology. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [61] Li A, et al. IFN-gamma promotes tau phosphorylation without affecting mature tangles. FASEB J. 2015;29(10):4384–98. source
  • Findingown data

    Among 26 mouse transcriptomic cohorts where Abi3 and Gngt2 were both differentially regulated, their expression changes were concordant in 24 studies.

    “In addition, we investigated 96 additional mouse transcriptomic datasets [33, 34] and in 26 of these cohorts, we found that Abi3 and Gngt2 were both differentially regulated. Among these 26 cohorts, Abi3 and Gngt2 expression changes were concordant in 24 studies (Additional File 6: Table S4), showing that these genes are consistently co-regulated across different mouse models and experimental”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [33] Wan YW, et al. Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 2020;32(2):107908. source
    • cites [34] Al-Ouran R, et al. A portal to visualize transcriptome profiles in mouse models of neurological disorders. Genes (Basel). 2019;10(10):759. source
  • Premisecitation

    The S209F variant of ABI3 (rs616338:p.Ser209Phe) increases risk of Alzheimer's disease (OR = 1.43, p = 4.5 × 10−10, MAF = 0.008).

    “The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer’s disease (AD)”
    • Also stated in: § Background · plain
      “The S209F ABI3 variant (rs616338:p.Ser209Phe) increased the risk of AD (OR = 1.43, p = 4.5 × 10−10, MAF = 0.008) [6, 7] and has been validated in a secondary study [8].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [6] Sims R, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373. source
    • cites [7] Conway OJ, et al. ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Mol Neurodegener. 2018;13(1):53. source

      The Results section ('Association of rs616338 and rs72824905 with AD'; page not provided) supports the stated direction of AD risk for ABI3 p.Ser209Phe. It reports OR = 1.41 and p = 0.044 for the complete Caucasian cohort, however, not the claim’s OR = 1.43, p = 4.5 × 10−10, or MAF = 0.008. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [8] Wightman DP, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276–82. source

      Table 1 (Functional enrichment of significantly associated regions; page unavailable) identifies ABI3 as an Alzheimer’s disease risk locus. It lists a different lead variant, rs28394864, and does not establish that S209F (rs616338) increases risk or support the quoted OR, P value, or MAF. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Bulk RNAseq data reveals increased levels of ABI3 RNA relative to control cohorts in both temporal cortex and cerebellum of human patients and in mouse models of amyloid and tau pathologies.

    “Bulk RNAseq data reveals increased levels of ABI3 RNA relative to control cohorts in both the temporal cortex and cerebellum of human patients and in mouse models of amyloid and tau pathologies [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Sims R, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373. source

      Online Methods > Gene Expression reports higher ABI3 RNA in AD temporal cortex than in controls before adjustment for cell-type markers; the difference is no longer significant after that adjustment. The paper also reports ABI3 up-regulation in two APP mouse models, but our copy does not report the claimed increase in cerebellum or in mouse models of tau pathology. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    In AD brains, ABI3 expression is significantly upregulated relative to controls (p = 4.47E-03).

    “In AD brains, ABI3 expression is significantly upregulated relative to controls (p = 4.47E-03) [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Sims R, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373. source

      The Online Methods > Gene Expression section reports significantly higher ABI3 expression in AD temporal cortex than in controls under the Simple model. It does not give the claimed p-value of 4.47E-03, and it says the difference is no longer significant after adjustment for brain cell-type markers. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 24

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

    Premisecitation

    Co-expression network analysis suggests a close functional relationship between ABI3 and at least two other AD-related microglial genes, TREM2 and SPI1.

    “co-expression network analysis suggests a close functional relationship with at least two other AD-related microglial genes, TREM2 and SPI1 [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Sims R, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373. source

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

    Premisecitation

    ABI3 has been reported to be a microglia-specific gene using single-cell RNAseq.

    “ABI3 has been reported to be a microglia-specific gene using single-cell RNAseq [12, 20].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [12] Yao Z, et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell. 2021;184(12):3222-3241 e26. source

      The Results section (‘Generation of the transcriptomic cell type taxonomy’; page unavailable) reports three microglia/perivascular macrophage clusters from single-cell transcriptomic data. It does not identify ABI3 as a microglia-specific gene. Searches for ‘ABI3’ and microglial markers found no passage addressing ABI3 expression or specificity. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [20] Zhang Y, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929–47. source

      The section 'An RNA-Seq transcriptome database of purified cell classes of the brain' describes RNA sequencing of purified mouse cortical cell populations, not single-cell RNA-seq. The passages on cell-specific genes identify other microglial markers, but a search for ABI3 and Abl interactor 3 found no passage reporting ABI3 as microglia-specific. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The S209F ABI3 variant has been validated in a secondary study.

    “and has been validated in a secondary study [8].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Wightman DP, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276–82. source

      The Functional enrichment table lists a significant Alzheimer’s disease association at the ABI3 locus (lead variant rs28394864), and Genome-wide inferences says the study replicated many previously identified loci. Our copy does not identify the S209F variant or establish that this specific variant was validated in the secondary study. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    These genes are reported to be associated with pathologic signatures in AD, most notably DAM and MGnD and PIG.

    “These genes are also reported to be associated with pathologic signatures in AD, most notably DAM and MGnD [24, 25] and PIG [21]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [24] Keren-Shaul H, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169(7):1276-1290 e17. source

      The Introduction and Discussion (page numbers unavailable) identify a DAM gene program associated with AD pathology, supporting the DAM portion. The passages from this paper do not identify an MGnD signature, so that portion is not supported by this source. PIG is cited separately in the citing sentence and is not assessed here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [25] Krasemann S, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47(3):566-581 e9. source
    • cites [21] Chen WT, et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell. 2020;182(4):976-991 e19. source

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

    Premisecitation

    In the brain, ABI3 expression has been reported to be enriched in microglia with ramified or amoeboid morphology.

    “In the brain, its expression has been reported to be enriched in microglia with ramified or amoeboid morphology [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Satoh JI, et al. Microglia express ABI3 in the brains of Alzheimer’s disease and Nasu-Hakola disease. Intractable Rare Dis Res. 2017;6(4):262–8. source

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

    Premisecitation

    Single-cell data from mouse brain suggests low level expression of Abi3 in microglia.

    “Single-cell data from mouse brain suggests low level expression in microglia ([12]; data available from: celltypes.brain-map.org).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Yao Z, et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell. 2021;184(12):3222-3241 e26. source

      The Results section (“Generation of the transcriptomic cell type taxonomy”; page unavailable) reports single-cell sampling of mouse-brain microglia, but does not report Abi3 expression or its level. Searches for “Abi3 microglia low expression” and microglial gene-expression data found no passage in our copy establishing the claimed low-level expression. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ABI3 is an AD risk gene.

    “Recent reports have confirmed ABI3 as an AD risk gene [6–8].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [6] Sims R, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373. source
    • cites [7] Conway OJ, et al. ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Mol Neurodegener. 2018;13(1):53. source

      The Results (Association of rs616338 and rs72824905 with AD) report an association between an ABI3 variant and AD in the combined Caucasian cohort. But the independent replication cohort and adjusted analysis did not reach statistical significance. The Conclusions say the findings strengthen the evidence for ABI3 as an AD risk factor, rather than definitively confirm it. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [8] Wightman DP, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276–82. source

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

    Premisecitation

    Crosstalk between AD risk immune genes has been demonstrated, notably between Cd33 and Trem2.

    “Crosstalk between AD risk immune genes has been recently demonstrated, notably between Cd33 and Trem2 [79].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [79] Griciuc A, et al. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer’s disease. Neuron. 2019;103(5):820-835 e7. source

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

    Premisecitation

    Abi3-Gngt2−/− microglia exhibit reduced surveillance of brain parenchyma.

    “Indeed, a recent study suggests that Abi3-Gngt2−/− microglia exhibits reduced surveillance of brain parenchyma [46].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [46] Simonazzi E, et al. Abi3 regulates microglial ramification and dynamic tissue surveillance in vivo. bioRxiv. 2021. https://www.biorxiv.org/content/10.1101/2021.03.19.436147v1 source

      The paper reports reduced surveillance of brain parenchyma by Abi3-KO microglia in awake mice (Abstract; page unavailable). It does not establish this finding for the Abi3-Gngt2−/− genotype named in the citing sentence; its methods describe Abi3-KO mice crossed with a Cx3cr1-EGFP reporter line (Two-photon microscopy; page unavailable). (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Wild type ABI3, but not S209F ABI3, migrated as a double band.

    “We observed that wild type ABI3, but not S209F ABI3 migrated as a double band (Fig. 10a) which is consistent with data reported earlier [44].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [44] Sekino S, et al. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015;13:41. source

      The Results (Chimeric analyses; page unavailable) discuss an Abi-1 Y213F mutant, not an ABI3 S209F mutant. Searches for S209F and double-band migration found no passage in our copy comparing wild-type and S209F ABI3 bands. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Absence of Abi3 alters microglial morphology and curbs homeostatic surveillance.

    “Another recent paper showed that absence of Abi3 (using the same models as used in this study) alters microglial morphology and curbs its function in homeostatic surveillance [46, 47].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [46] Simonazzi E, et al. Abi3 regulates microglial ramification and dynamic tissue surveillance in vivo. bioRxiv. 2021. https://www.biorxiv.org/content/10.1101/2021.03.19.436147v1 source
    • cites [47] Karahan H, 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. source

      The Results section reports fewer microglia around plaques in Abi3−/− 5XFAD mice and impaired migration after ABI3 knockdown in cultured microglia. It does not report altered microglial morphology or directly show that Abi3 absence curbs homeostatic surveillance; the Discussion mentions surveillance only as background on actin polymerization. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Alterations in gliosis, especially astrocyte dysfunction, impact synaptic health.

    “Alterations in gliosis, especially astrocyte dysfunction, impacts synaptic health [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Liu CY, et al. Emerging roles of astrocytes in neuro-vascular unit and the tripartite synapse with emphasis on reactive gliosis in the context of Alzheimer’s disease. Front Cell Neurosci. 2018;12:193. source

  • May combine two claims.

    Findingcitation

    Parental Abi3-Gngt2−/− lines show an abundance of immune signature, while TG-Abi3-Gngt2−/− mice show additional signatures consistent with ABI family functions.

    “While the parental Abi3-Gngt2−/− lines mostly indicated an abundance of immune signature, the TG-Abi3-Gngt2−/− mice showed additional signatures consistent with the known functions of the ABI family of proteins [37].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Mendoza MC. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin Cell Dev Biol. 2013;24(4):272–9. source

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

    Premisecitation

    YKL-40 has non-cell autonomous activity affecting microglial function, circadian clock, and AD progression.

    “Recently YKL-40 has been shown to have non-cell autonomous activity in the brain, affecting microglial function, circadian clock, and generally AD progression [75].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [75] Lananna BV, et al. Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis. Sci Transl Med. 2020;12(574):eaax3519. source

      The Discussion reports that Chi3l1 deletion changes microglial phagocytosis and is associated with reduced amyloid plaques; it also reports an association between lower human YKL-40 and slower AD progression. But it says the microglial effect may be cell-autonomous, not that non-cell-autonomous activity was established. The Introduction says the astrocyte circadian clock regulates Chi3l1 expression, rather than YKL-40 affecting the clock. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The plum3 module is enriched for immune function, with cd37 hub gene related to a Tyrobp-regulated microglial module in AD and Lat2 identified as a core transcriptional signature of AD microglia.

    “This module is especially enriched for immune function, with the cd37 hub gene related to a Tyrobp-regulated microglial module in AD [41] and Lat2 identified as a core transcriptional signature of AD microglia [42].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [41] Zhang B, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153(3):707–20. source

      The Results section, under “Highlighting the Microglia Pathway with TYROBP as Causal Regulator” (page unavailable), identifies TYROBP as a key regulator of an immune/microglia network in late-onset Alzheimer’s disease. Our copy does not identify CD37 or establish its relationship to that network (searched: CD37). The Lat2 statement has a separate citation and is not assessed against this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [42] Patir A, et al. A core transcriptional signature of human microglia: derivation and utility in describing region-dependent alterations associated with Alzheimer’s disease. Glia. 2019;67(7):1240–53. source

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

    Premisecitation

    YKL-40 is primarily an astrocytic protein elevated in AD and considered a potential biomarker.

    “YKL-40 is primarily an astrocytic protein that is elevated in AD and is considered a potential biomarker [74].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [74] Craig-Schapiro R, et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol Psychiatry. 2010;68(10):903–12. source

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

    Premisecitation

    Hippocampal IL-1β expression reduces plaques in APP/PS1 and 3xTg-AD models but worsens tauopathy in 3xTg-AD.

    “Hippocampal expression of IL-1β was shown to robustly reduce plaques in the APP/PS1 model and 3xTg-AD model but worsened tauopathy in the 3xTg-AD model [62, 63].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [62] Shaftel SS, et al. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest. 2007;117(6):1595–604. source
    • cites [63] Ghosh S, et al. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci. 2013;33(11):5053–64. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ levels are generally well-correlated with immune activation indicated by microgliosis and astrocytosis.

    “Aβ levels are generally well-correlated with immune activation indicated by microgliosis and astrocytosis [3].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Kinney JW, et al. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:575–90. source

      The Microglia section (page unavailable) links Aβ to microglial activation and describes reactive microgliosis alongside Aβ accumulation. The Specific cytokine signaling in AD section (page unavailable) places reactive gliosis around Aβ plaques, but the copy does not establish that Aβ levels are generally well-correlated with both microgliosis and astrocytosis. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    C terminally FLAG-tagged ABI3 has been previously shown to be functionally active.

    “C terminally FLAG-tagged ABI3 has been previously shown to be functionally active [44].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Sekino S, et al. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015;13:41. source

      The Results section ('Ectopic expression of NESH/Abi-3 perturbed the formation of lamellipodial protrusions'; page unavailable) reports a functional effect of FLAG-tagged NESH/Abi-3, also called ABI3. But Methods ('Expression plasmids'; page unavailable) specifies an N-terminal FLAG tag, not the C-terminal tag claimed. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Activated micro/astroglia enhances Aβ phagocytosis.

    “For amyloid pathology, there is data that activated micro/astroglia enhances Aβ phagocytosis [60, 62, 71]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [60] Chakrabarty P, et al. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J Immunol. 2010;184(9):5333–43. source

      The Results section reports increased uptake of fibrillar Aβ42 by mouse microglia primed with IFN-γ in vitro. This supports the microglial part of the claim, but the cited passages do not show enhanced Aβ phagocytosis by astroglia. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [62] Shaftel SS, et al. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest. 2007;117(6):1595–604. source

      The Discussion says activated microglia overlapped more with plaques and that this could potentially increase plaque phagocytosis; it does not demonstrate increased phagocytosis. The neuroinflammatory-phenotype section reports astrocyte activation but does not link astrocytes to Aβ phagocytosis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [71] Chakrabarty P, et al. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 2010;24(2):548–59. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Phosphorylation of Abi family proteins is related to their stability and function.

    “Since, phosphorylation of Abi family of proteins is related to their stability and function [45]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Huang CH, et al. The involvement of Abl and PTP61F in the regulation of Abi protein localization and stability and lamella formation in Drosophila S2 cells. J Biol Chem. 2007;282(44):32442–52. source

      The results section on Abl phosphorylation reports that an Abi phosphorylation-site mutant had a shorter half-life and was less effective than wild-type Abi at restoring normal lamella formation in Drosophila S2 cells. This supports a relationship between phosphorylation, stability, and function for the Abi protein studied, but does not establish it for Abi family proteins generally. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The ABI family proteins, especially ABI-1 and ABI-2, are involved in cytoskeletal reorganization.

    “The ABI family of proteins, especially ABI-1 and ABI-2, are involved in cytoskeletal reorganization [37].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Mendoza MC. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin Cell Dev Biol. 2013;24(4):272–9. source

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

    Premisecitation

    The PIG profile is concordant with high Aβ burden, independent of tau, and overlaps with ALS co-expression network changes.

    “Originally, the PIG profile was found to be concordant with high Aβ burden, independent of tau, and also overlapping with co-expression network changes identified in ALS [21].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Chen WT, et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell. 2020;182(4):976-991 e19. source

      The PIGs identification section reports that PIGs expression increases with Aβ accumulation, and the reproducibility section reports significant overlap with an ALS microglial co-expression submodule. That section describes the amyloid-responsive networks as having minimal correlation with tau pathology; it does not establish complete independence from tau, as the claim states. Page numbers are not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Chil1/CHI3L1/YKL-40, the top hub gene in honeydew1, is related to inflammation and AD pathophysiology.

    “Notably, Chil1/CHI3L1/YKL-40 (Chitinase-like 1) that is the top hub gene in honeydew1 is related to inflammation and AD pathophysiology [39].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Llorens F, et al. YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias. Mol Neurodegener. 2017;12(1):83. source

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

    Premisecitation

    Cx3cr1 deficiency reduces amyloid deposition in APP models but aggravates tau hyperphosphorylation in hTau mice.

    “Similarly, deficiency of Cx3cr1 reduced amyloid deposition in two different APP models but aggravated tau hyperphosphorylation in hTau mice [65, 66].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [65] Bhaskar K, et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31. source
    • cites [66] Lee S, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177(5):2549–62. source

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

    Premisecitation

    Phosphorylation is key to maintaining stability and function of ABI family proteins.

    “It is known that phosphorylation is key to maintaining the stability and function of ABI family of proteins [37, 80].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [37] Mendoza MC. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin Cell Dev Biol. 2013;24(4):272–9. source

      Section 2.1 (Abl) reports that Abl phosphorylation promotes Drosophila ABI1 stability, while oncogenic Abl induces ABI2 degradation; it also cautions that Abl activity alone is unlikely to regulate ABI stability. Section 3.2 (ERK) links ABI phosphorylation to WRC activation. These passages support roles for phosphorylation in ABI stability and function, but not the unqualified claim that it maintains the stability of ABI family proteins generally. Page numbers were not provided in the passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [80] Courtney KD, et al. Localization and phosphorylation of Abl-interactor proteins, Abi-1 and Abi-2, in the developing nervous system. Mol Cell Neurosci. 2000;16(3):244–57. source

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

    Findingown data

    The antiquewhite2 module was highly associated with several immune and autoimmune conditions such as Staphylococcus infection and primary immunodeficiency as well as neurodegenerative diseases such as prion disease.

    “It was also highly associated with several immune and autoimmune conditions such as Staphylococcus infection and primary immunodeficiency as well as neurodegenerative diseases such as prion disease”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Abi3 and Gngt2 genes are co-regulated in APP transgenic TgCRND8 mice (ρ = 0.625, p = 7.31e−06) and in MAPT transgenic rTg4510 mice (ρ = 0.554, p = 0.018).

    “We also confirmed that Abi3 and Gngt2 genes are co-regulated in the APP transgenic TgCRND8 mice (Fig. 2d, ρ = 0.625, p = 7.31 − 06) and in MAPT transgenic rTg4510 mice (Fig. 2e, ρ = 0.554, p = 0.018).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Abi3 mRNA levels consistently increased in human AD and APP transgenic mouse model, but not in a MAPT transgenic model.

    “RNAseq data revealed that Abi3 mRNA levels consistently increased in human AD and APP transgenic mouse model, but not in a MAPT transgenic model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In MAPT transgenic rTg4510 mice, Abi3 RNA levels increased in 4.5-month-old tau expressing mice but reduced to levels comparable to nonTG littermates at 6 months.

    “In MAPT transgenic rTg4510 mice, the RNA levels of Abi3 increased in 4.5-month-old tau expressing mice but reduced to levels comparable to nonTG littermates at 6 months (Fig. 1b; Additional File 3: Table S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Abi3−/− mice, both Abi3 and its overlapping gene Gngt2 are disrupted.

    “document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice.”
    • Also stated in: § ABI3 and GNGT2 genes are co-regulated in APP mouse models and in AD · plain
      “Using data from UCSC genome browser, we discovered that the Velocigene targeted deletion in the Abi3 locus knocked out both Abi3 and Gngt2”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TG-Abi3-Gngt2−/− mice over time show dysfunctional immune phenotype, age-dependent reduction of beneficial effect on Aβ, and accumulation of ptau.

    “The TG-Abi3-Gngt2−/− mice also, over time, showed dysfunctional immune phenotype, with age-dependent reduction of beneficial effect on Aβ and accumulation of ptau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Iba-1-reactive microglia in control vector injected Abi3-Gngt2−/− mice was comparable (6 months) or lower than (3 months) P301L/S320F tau expressing WT Abi3-Gngt2+/+ mice.

    “Notably, Iba-1-reactive microglia in the control vector injected Abi3-Gngt2−/− mice was comparable (6 months) or lower than (3 months) P301L/S320F tau expressing WT Abi3-Gngt2+/+ mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Loss of Abi3-Gngt2 reduces amyloid pathology in mice, but this effect diminishes with age.

    “Loss of this locus results in a reduction in amyloid pathology and preservation of synaptic markers, though effects on amyloid are diminished as the mice age.”
    • Also stated in: § Discussion · plain
      “reduce Aβ plaques in a gene dose- and age-dependent manner in TgCRND8 mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 9-month-old TG-Abi3-Gngt2+/− mice compared with age-matched TG-Abi3-Gngt2+/+ mice, no changes in Aβ burden, astrocytosis, microgliosis, or ubiquitin staining patterns were found.

    “We found no changes in Aβ burden, astrocytosis (GFAP), microgliosis (Iba-1 and cd11b), or ubiquitin staining patterns between these two cohorts of mice at this age”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 6 months of age, astrocytosis differences normalized in the cortex but hippocampal GFAP burden in TG-Abi3-Gngt2+/− mice was higher than both TG-Abi3-Gngt2+/+ or TG-Abi3-Gngt2−/− mice.

    “At 6 months of age, these differences normalized in the cortex but hippocampal GFAP burden in TG-Abi3-Gngt2+/− mice was higher than both TG-Abi3-Gngt2+/+ or TG-Abi3-Gngt2−/− mice”
    Quote in the paperSubstantial claim

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

    Findingown data

    Patterns of ubiquitin staining around plaques appeared unchanged across the Abi3 genotypes.

    “The patterns of ubiquitin staining around plaques appeared unchanged across the Abi3 genotypes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Outcomes of Abi3-Gngt2 deletion on amyloid pathology are determined by age and gene dose.

    “The outcomes of Abi3-Gngt2 deletion on amyloid pathology was determined by age as also gene dose, which is consistent with studies on Trem2 models of AD [49, 57].”
    Quote in the paperSubstantial claim

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

    Findingown data

    No major changes in ubiquitin labeling of Aβ plaques were observed across all Abi3 genotypes.

    “We did not observe major changes in ubiquitin labeling of the Aβ plaques across all the Abi3 genotypes”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Relative to TG-Abi3-Gngt2+/+ mice, TG-Abi3-Gngt2−/− mice showed lower Abi3 and Gngt2 as expected.

    “Relative to the TG-Abi3-Gngt2+/+ mice, the TG-Abi3-Gngt2−/− mice showed lower Abi3 and Gngt2 as expected”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In 3-month-old WT tau cohorts, no differences in total tau or ptau levels between Abi3-Gngt2−/− and Abi3-Gngt2+/+ mice, nor induction of MC1-reactive pretangle tau, were found.

    “In the 3-month-old cohorts, we did not find any differences in the total tau levels or ptau levels of Abi3-Gngt2−/− and Abi3-Gngt2+/+ mice (Additional File 11: Fig. S7d-g), nor did we see any induction of MC1-reactive pretangle tau”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Abi3 is expressed in microglia and also in other cells in human and APP transgenic mouse brain.

    “Here we document that Abi3, though primarily expressed in microglia, is also expressed in other cells in humans and APP transgenic mice brain”
    • Also stated in: § Discussion · hedged
      “Our in situ hybridization data indicates that ABI3 is present in both microglia and neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the 6-month-old WT tau cohort, tau expression levels were comparable, but ptau levels were higher in Abi3-Gngt2−/− mice relative to Abi3-Gngt2+/+ mice (p < 0.0001).

    “In the 6-month-old cohort, while the levels of tau expression were comparable (Additional File 11: Fig. S7l-m), we noticed higher ptau levels in Abi3-Gngt2−/− mice relative to Abi3-Gngt2+/+ mice (p < 0.0001)”
    Quote in the paperSubstantial claim

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

    Premisecitation

    RNA levels do not always reflect protein levels.

    “Given that protein levels in any specific cell cannot always be inferred from RNA levels [77]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell. 2016;165(3):535–50. source

  • May combine two claims.

    Interpretationown data

    Presence of phenylalanine at position 209 specifically impairs overall ABI3 phosphorylation, though auto-phosphorylation at this site is not necessary.

    “This shows that presence of phenylalanine at position 209 specifically impairs overall ABI3 phosphorylation, though auto-phosphorylation at this site is not necessary.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Loss of Abi3-Gngt2 function leads to early induction of immunity that could lead to detrimental outcomes in the longer term.

    “Overall, this would suggest that loss of Abi3-Gngt2 function leads to early induction of immunity that could lead to detrimental outcomes in the longer term (Fig. 11).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The immune-related phenotypes in Abi3-Gngt2−/− mice are primarily driven by the loss of Abi3 and/or Gngt2 rather than environmental factors.

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

    Study design and conductreasoning

    Gene deletion studies may miss subtle physiological insights when genes have complex disease-stage- or age-dependent outcomes.

    “In addition, gene deletion studies may also miss subtle physiological insights when such genes have complex disease-stage- or age-dependent outcomes, such as having both gain and loss of function phenotype with respect to different aspects of brain homeostasis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The locus deletion in the mice affected two genes with overlapping sequences.

    “a limitation of our study is that the locus deletion in the mice used in this study affected two genes that have overlapping sequences.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The effect of Abi3-Gngt2 deletion on Aβ and tau was inferred using independent, stand-alone models.

    “Another limitation is we have inferred the effect of Abi3-Gngt2 deletion on Aβ and tau using independent, stand-alone models”
    Quote in the paperNot a substantial claim
49 of 49

  • The authors state this as an assumption.

    Non-Iba1 cells in grey matter are neurons.

    “which are presumed to be neurons based on size and location”

  • The paper relies on this without support.

    Abi3-Gngt2−/− mice lack Aβ at baseline.

    “even in the absence of Aβ”
    “in spite of reduced Aβ plaques”

  • The paper relies on this without support.

    The effects of Abi3-Gngt2 deletion on amyloid and tau pathology observed in separate mouse models are relevant to the combined Aβ and tau pathologies of AD.

    “Another limitation is we have inferred the effect of Abi3-Gngt2 deletion on Aβ and tau using independent, stand-alone models and thus, how this could affect AD phenotype, which is characterized by combinatorial Aβ and tau pathologies, still needs to be characterized.”

  • The paper relies on this without support.

    The immune-related phenotypes in Abi3-Gngt2−/− mice are primarily driven by the loss of Abi3 and/or Gngt2 rather than environmental factors.

    “In fact, immune-related phenotypes, as inherent in this Abi3-Gngt2−/− mice, are extremely sensitive to environmental factors and local immune stressors that can regulate metabolic homeostasis and modulate CNS health [53].”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The AD-associated S209F mutation is located adjacent to a critical phosphorylation site (Ser209) that regulates ABI3 function.

    “The AD‐associated S209F mutation, located adjacent to a critical phosphorylation site (Ser209) that regulates ABI3 function, is a key PTM that increases the risk of AD. 18”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [18]

    The Results section (“AD-associated mutation alters ABI3 phosphorylation”) identifies S209F as a substitution at position 209, not a mutation adjacent to Ser209. It reports that the substitution impairs overall ABI3 phosphorylation but says phosphorylation at that site is not necessary; it does not establish Ser209 as a critical phosphorylation site regulating ABI3 function. (LLM, conf=0.89)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • As demonstrated in prior studies, several genes were significantly downregulated in the Abi3-/- mouse model, including Gngt2 and Gm10039.

    “As we and others demonstrated in prior studies (22, 23), several genes were significantly downregulated in the Abi3-/- mouse model, including the Gngt2 and Gm10039.”

    From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [23]

    The Results section (‘ABI3 and GNGT2 genes are co-regulated in APP mouse models and in AD’; page unavailable) reports that Gngt2 expression was dramatically reduced in the knockout mice. The Results section on reactive gliosis also lists Gngt2 among downregulated RNAs. Our copy does not mention Gm10039, so it does not support that part of the claim. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The S209F mutation is a key PTM that increases the risk of AD.

    “The AD‐associated S209F mutation, located adjacent to a critical phosphorylation site (Ser209) that regulates ABI3 function, is a key PTM that increases the risk of AD. 18”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [18]

    The Background reports that the S209F ABI3 variant increases AD risk. The Results show that this mutation impairs ABI3 phosphorylation, but do not identify the mutation itself as a post-translational modification (PTM); they place the substitution at position 209, not adjacent to Ser209. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Serine 209 (Ser 209) of ABI3 is a phosphorylatable residue.

    “Serine 209 (Ser 209) of ABI3 is a phosphorylatable residue; mutation to phenylalanine (Phe) abolishes this phosphorylation capacity. 18”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [18]

    The Results section (‘AD-associated mutation alters ABI3 phosphorylation’; page not supplied) shows that wild-type ABI3 is phosphorylated and that S209F impairs its overall phosphorylation. It does not establish that Ser 209 itself is phosphorylated, and it describes a phosphorylation deficit rather than complete abolition. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Mutation of Ser209 to Phe abolishes phosphorylation capacity.

    “mutation to phenylalanine (Phe) abolishes this phosphorylation capacity. 18”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [18]

    The Results section (“AD-associated mutation alters ABI3 phosphorylation”) reports that S209F lacks the phosphorylated upper band seen for wild-type ABI3, but concludes that phenylalanine at position 209 impairs overall phosphorylation. The Discussion describes a dramatic reduction in self-phosphorylation, not abolition of all phosphorylation capacity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Ibanez, K. R., McFarland, K. N., Phillips, J., Allen, M., Lessard, C. B., Zobel, L., De La Cruz, E. G., Shah, S., Vo, Q., Wang, X., Quicksall, Z., Ryu, D., Funk, C., Ertekin-Taner, N., Prokop, S., Golde, T. E., & Chakrabarty, P.
Affiliations
  • University of Florida (US)
  • Mayo Clinic (US)
  • Institute for Systems Biology (US)
Corresponding author
Chakrabarty, Paramita
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-07-27
Volume
14
Issue
1
Pages
104-104
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-022-01044-1
PMC
PMC9327202
OpenAlex
W4288725055
Cited by
18
References
94
Citations by year
2026: 4 · 2025: 7 · 2024: 1 · 2023: 5 · 2022: 1
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (U01 AG046139)
  • State of Florida Ed & Ethel Moore Alzheimer’s Disease Research Program (8AZ16)
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
ABI3, Alzheimer's disease, amyloid-beta, tau pathology, microglia, astrocyte activation, APP transgenic mice, TREM2, PLCγ2, TYROBP, gene dosage
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Brain, Disease Models, Animal, Gliosis, Humans, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, GTP-Binding Protein gamma Subunits, Adaptor Proteins, Signal Transducing, 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 2026-11-02.

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

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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