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Cited by 16Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology

Open access
Messenger, Evan J., Baar, Sydney A., Bedford, Logan M., Tsai, Andy P., Lin, Peter Bor‐Chian, Ferguson, Chloe A., Xu, Guixiang, Wallace, Abigail +3 more·2025·Alzheimer's & Dementia
DOI 10.1002/alz.70231PMC PMC12064341
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Abstract

BACKGROUND: Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2). Variants which alter PLCG2 activity impact Alzheimer's disease (AD) risk, but the effects of PLCG2 deficiency in AD remain unclear. METHODS: 5xFAD mice were crossed with PLCG2‐ and TREM2‐deficient mice to assess the role of PLCG2 in response to amyloid pathology. Human bulk RNA‐sequencing data were used to validate findings in AD patients. RESULTS: In 5xFAD mice, the absence of PLCG2 resulted in reduced TREM2 expression and impaired microglial associations with amyloid beta plaques. Transcriptomic analysis revealed perturbations in immune‐related pathways shared between PLCG2 and TREM2 deficiencies, as well as distinct differences. Human transcriptomics revealed positive correlations between PLCG2 and TREM2 independent of pathological scores. DISCUSSION: PLCG2 is a critical component of TREM2 signal transduction and may play an upstream role in TREM2 regulation. These findings clarify the mechanisms of risk and protective PLCG2 variants. Highlights: The role of phospholipase C gamma 2 (PLCG2) deficiency in response to amyloid beta (Aβ) pathology was investigated in 5xFAD mice and with human cortical transcriptomics. PLCG2 deficiency significantly reduces triggering receptor expressed on myeloid cells 2 (TREM2) expression, while TREM2 deficiency increases PLCG2 expression. PLCG2 expression predicts TREM2 expression in human cortex independent of pathology. PLCG2 and TREM2 deficiencies similarly impair microglial responses to Aβ plaques, exacerbate neuronal pathology, and impair gene expression associated with immune responses. PLCG2 deficiency confers distinct transcriptional perturbations from TREM2 deficiency. PLCG2 may play an upstream role in the regulation of the TREM2‐mediated immune response.

AI snapshot

Written from the paper’s full text.

TL;DR

In 5xFAD mice, PLCG2 deficiency reduced TREM2 expression and impaired microglial association with amyloid-beta plaques, while TREM2 deficiency increased PLCG2 expression. Human cortical transcriptomics showed PLCG2 expression positively predicts TREM2 expression independent of AD pathological scores, suggesting PLCG2 may act upstream in TREM2 regulation.

Key findings

  • In 7.5-month-old 5xFAD mice, PLCG2 deficiency prevented the amyloid-associated increase in TREM2 protein and significantly reduced TREM2 mRNA versus 5xFADWT; TREM2 deficiency increased PLCG2 protein.
  • PLCG2 and TREM2 deficiencies similarly increased average X34+ plaque size, impaired microglial plaque coverage/engagement, and increased LAMP1+ dystrophic neurite area per X34+ plaque (significant only in TREM2-deficient animals); both also showed smaller average MOAB2+ plaque sizes.
  • Bulk RNA-seq identified 1256 DEGs for 5xFAD Plcg2−/− versus 5xFADWT and 1002 DEGs for 5xFAD Trem2−/− versus 5xFADWT; shared DEGs were enriched for immune-response pathways, and Itgax, Clec7a, and Cd68 were reduced in both.
  • In human MSBB bulk RNA-seq (>200 patients; Brodmann areas 10, 22, 36, 44), PLCG2 expression predicted TREM2 expression in nearly all regions surveyed regardless of CERAD, Braak, or CDR score, and correlations remained after AIF1 normalization.

Methods

  • 5xFAD mice were crossed with PLCG2-deficient and TREM2-deficient mice; 7.5-month-old cortex was analyzed by immunofluorescence, immunoblotting, qPCR, and bulk RNA-seq (n = 6 per group for RNA-seq/imaging: 3M/3F for 5xFADWT and 5xFAD Trem2−/−, 4M/2F for 5xFAD Plcg2−/−; n = 4 per group for immunoblot).
  • Human bulk RNA-seq data from the Mount Sinai Brain Bank (MSBB) were used with clinical and neuropathological scores; linear regression tested whether PLCG2 expression predicted TREM2 expression, including after normalization to AIF1.
  • Differential expression used edgeR with FDR-adjusted p ≤ 0.05 and absolute log2 fold change ≥ 0.6; GO enrichment used DAVID; PCA/heatmaps used ClustVis.

Limitations

  • Stated: only six 5xFAD;homozygous PLCG2 knockout mice were obtained due to breeding difficulty and unclear non-Mendelian inheritance; the authors cannot rule out developmental/homeostatic contributions of PLCG2 deficiency; bulk RNA-seq cannot assess cell type–specific expression; findings at 7.5 months may not generalize across disease stages; future high-powered studies are needed to clarify sex effects.
  • Stated: TREM2 depletion effects depend on disease stage, and PLCG2 depletion should be investigated across a greater age range.
  • Evident from the text: the PLCG2 knockout group was small and sex-imbalanced (4 male/2 female for RNA-seq; n = 4 for immunoblot), large sex effects on plaque deposition were noted, human data are bulk correlational rather than causal, and the shared DEG count is reported inconsistently (469 shared in Results vs 578 shared in Discussion).

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

Integrity signals

Registry

Crossref · 10.1002/alz.70231

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

71 of 83 cited sources checked · 28 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    PLCG2 loss-of-function has recently been associated with worsened AD pathology.

    “Likewise, PLCG2 loss‐of‐function has recently been associated with worsened AD pathology. 12 , 27 , 29”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [12] Tsai AP, Dong C, Lin PBC, et al. PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome Med. 2022; 14: 17. 35180881 PMC8857783 source

      The Conclusions (page unavailable) say future studies are needed to determine whether decreased PLCG2 expression exacerbates or attenuates disease. The paper studies Plcg2-inactivated mice, but does not report that loss of function is associated with worsened AD pathology. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [27] Tsai AP, Dong C, Lin PB‐C, et al. Genetic variants of phospholipase C‐γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease. Immunity. 2023; 56: 2121‐ 2136.e6. 37659412 PMC10564391 source
    • cites [29] Oblak AL, Kotredes KP, Pandey RS, et al. Plcg2M28L interacts with high fat/high sugar diet to accelerate Alzheimer's disease‐relevant phenotypes in mice. Front Aging Neurosci. 2022; 14: 886575. 35813947 PMC9263289 source

      The Discussion reports more extreme AD-relevant phenotypes in mice carrying Plcg2M28L on a LOAD1 background when exposed to a high-fat/high-sugar diet. It describes loss of function for this variant as predicted, not established. Thus the paper supports a qualified association in this mouse model, but not the broader claim that PLCG2 loss of function generally worsens AD pathology. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    A significant proportion of AD-linked genes are associated with microglia and the immune response.

    “A significant proportion of these AD‐linked genes are associated with microglia and the immune response, reinforcing the necessity to understand the intersection of immunity and AD pathogenesis in the development of novel AD therapeutics.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [6] Khani M, Gibbons E, Bras J, Guerreiro R. Challenge accepted: uncovering the role of rare genetic variants in Alzheimer's disease. Mol Neurodegener. 2022; 17: 3. 35000612 PMC8744312 source
    • cites [7] Kunkle BW, Grenier‐Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta‐analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019; 51: 414‐ 30. 30820047 PMC6463297 source
    • cites [8] Nott A, Holtman IR, Coufal NG, et al. Brain cell type–specific enhancer–promoter interactome maps and disease‐risk association. Science. 2019; 366(6469): 1134‐ 1139. 31727856 PMC7028213 source
  • Premisecitation

    Genetic variants of PLCG2 are associated with altered risk for AD.

    “Genetic variants of PLCG2 are associated with altered risk for AD, and mutations which alter its function result in pleiotropic effects impacting immune, vascular, and nervous functions, as well as contributing to cancer pathogenesis and treatment resistance.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Jackson JT, Mulazzani E, Nutt SL, Masters SL. The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration. J Biol Chem. 2021; 297: 100905. 34157287 PMC8318911 source
    • cites [11] Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial‐mediated innate immunity in Alzheimer's disease. Nat Genet. 2017; 49: 1373‐ 84. 28714976 PMC5669039 source
  • Premisecitation

    PLCG2 is an intracellular effector of microglial cell surface receptors, including TREM2.

    “Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [10] Jackson JT, Mulazzani E, Nutt SL, Masters SL. The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration. J Biol Chem. 2021; 297: 100905. 34157287 PMC8318911 source
    • cites [11] Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial‐mediated innate immunity in Alzheimer's disease. Nat Genet. 2017; 49: 1373‐ 84. 28714976 PMC5669039 source
    • cites [12] Tsai AP, Dong C, Lin PBC, et al. PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome Med. 2022; 14: 17. 35180881 PMC8857783 source
  • Premisecitation

    Recent studies have identified a role for gene dosage in microglial genes, including TREM2, whereby partial and complete loss of gene expression resulted in divergent phenotypic consequences.

    “Surprisingly, recent studies have identified a role for gene dosage in microglial genes, including TREM2, whereby partial and complete loss of gene expression resulted in divergent phenotypic consequences, emphasizing the importance of exploring total PLCG2 loss.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [30] Codocedo JF, Mera‐Reina C, Bor‐Chian Lin P, et al. Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression. Cell Rep. 2024; 43: 114488. 39002124 PMC11398604 source
    • cites [31] Sayed FA, Telpoukhovskaia M, Kodama L, 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: 10172‐ 7. 30232263 PMC6176614 source
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    PLCG2 is expressed principally by immune cells, including myeloid lineage cells, B cells, and other lymphocytes, and in the brain is inducibly expressed by plaque-associated microglia.

    “PLCG2 is expressed principally by immune cells, including myeloid lineage cells, B cells, and other lymphocytes, and in the brain is inducibly expressed by plaque‐associated microglia.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [10] Jackson JT, Mulazzani E, Nutt SL, Masters SL. The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration. J Biol Chem. 2021; 297: 100905. 34157287 PMC8318911 source

      The Abstract and the sections on innate and adaptive immunity describe PLCγ2 activity in hematopoietic, myeloid, and B cells. The neurological diseases section says it is primarily expressed in brain microglia and reports increased PLCG2 expression in the cortex of an Alzheimer’s mouse model. It does not establish that expression is inducible specifically in plaque-associated microglia. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [11] Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial‐mediated innate immunity in Alzheimer's disease. Nat Genet. 2017; 49: 1373‐ 84. 28714976 PMC5669039 source

      The paper states that PLCG2 is expressed in brain microglia and reports high expression in peripheral monocytes, spleen, and whole blood (Online Methods, Gene Expression; page unavailable). It does not specifically establish expression in B cells or other lymphocytes. It also reports higher PLCG2 expression in Alzheimer’s cortex, but says this appears related to microgliosis rather than showing inducible expression in plaque-associated microglia. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [12] Tsai AP, Dong C, Lin PBC, et al. PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome Med. 2022; 14: 17. 35180881 PMC8857783 source

      The Results section on 5xFAD mice reports increased Plcg2 expression that returned to control levels when microglia were reduced; the Discussion links the increase to amyloid plaques and plaque-associated microglia. Our copy does not establish the broader claim that PLCG2 is expressed principally by immune cells, including B cells and other lymphocytes (searched for those cell types). No page numbers were provided. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the brain, there exists a remarkably tight window whereby a modest increase in PLCG2 enzymatic activity is associated with protective effects while reduced or robust increases in activity prove detrimental.

    “Interestingly, in the brain, there exists a remarkably tight window whereby a modest increase in enzymatic activity is associated with protective effects while reduced or robust increases in activity prove detrimental.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Magno L, Bunney TD, Mead E, Svensson F, Bictash MN. TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation. Mol Neurodegener. 2021; 16: 22. 33823896 PMC8022522 source

      The section on clinical phenotypes says the mildly activating PLCG2 p.P522R variant is associated with protection against neurological symptoms. It also says too little or too much PLCγ2 activity is detrimental to immune function, but notes that this is documented primarily in the periphery. It explicitly describes a detrimental effect of reduced PLCγ2 function in brain immune cells as speculative, with convincing data lacking; it therefore does not establish the claimed tight window in the brain. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] Siraliev‐Perez E, Stariha JTB, Hoffmann RM, et al. Dynamics of allosteric regulation of the phospholipase C‐gamma isozymes upon recruitment to membranes. Elife. 2022; 11: e77809. 35708309 PMC9203054 source

      The Introduction (page not provided) reports that a putative gain-of-function PLC-γ2 variant is associated with lower Alzheimer’s disease risk and may slow cognitive decline. It does not establish that the activity increase is modest, define a tight protective window, or say that reduced or robustly increased activity is detrimental in the brain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The mildly hypermorphic PLCG2P522R variant is associated with increased longevity, improved clearance of Aβ, and protection against AD.

    “With respect to AD, the mildly hypermorphic PLCG2P522R variant is associated with increased longevity, improved clearance of Aβ, and protection against AD.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [22] Claes C, England WE, Danhash EP, et al. The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model. Alzheimers Dement. 2022; 18: 1765‐ 78. 35142046 PMC9360195 source

      The Narrative (page unavailable) describes P522R as mildly hypermorphic and associated with reduced risk of late-onset AD. It does not establish increased longevity: its reference to improved survival concerns cellular effects, not lifespan. The Detailed results (page unavailable) found no significant increase in amyloid internalization or reduction in plaque burden in the chimeric AD mice, so improved Aβ clearance is not supported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [23] Diks AM, Teodosio C, de Mooij B, et al. Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system. Mol Neurodegener. 2023; 18: 25. 37081539 PMC10116473 source

      The Background links p.P522R to increased likelihood of extreme longevity and lower Alzheimer’s disease risk, and the Discussion describes it as a slight gain-of-function variant. The paper does not report improved Aβ clearance: its Discussion instead reports slightly reduced phagocytosis in carriers’ myeloid cells and only speculates about more efficient clearance of brain tissue damage and debris. No page numbers are available in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [24] Kleineidam L, Chouraki V, Próchnicki T, et al. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta Neuropathol. 2020; 139: 1025‐ 1044. 32166339 PMC7244617 source

      The Introduction reports that p.P522R slightly increases PLCG2 activity, is associated with protection against AD, and has been suggested to have a positive effect on longevity. The Discussion and Results do not support improved Aβ clearance: they report no association with Aβ1-42 pathology and place the observed protective effect downstream of amyloid accumulation, chiefly through reduced tau pathology. Page numbers are not available in our copy. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

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

    Premisecitation

    At the membrane, PLCG2 hydrolyzes PIP2 into IP3 and DAG.

    “At the membrane, it hydrolyzes the lipid phosphatidylinositol (4,5)‐bisphosphate (PIP2) into the second messengers inositol (1,4,5)‐trisphosphate (IP3) and diacylglycerol (DAG).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Magno L, Bunney TD, Mead E, Svensson F, Bictash MN. TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation. Mol Neurodegener. 2021; 16: 22. 33823896 PMC8022522 source
    • cites [14] Siraliev‐Perez E, Stariha JTB, Hoffmann RM, et al. Dynamics of allosteric regulation of the phospholipase C‐gamma isozymes upon recruitment to membranes. Elife. 2022; 11: e77809. 35708309 PMC9203054 source

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

    Premisecitation

    Upon tyrosine phosphorylation by upstream receptor complexes, PLCG2 undergoes an activating conformational change and is recruited to the plasma membrane.

    “Upon tyrosine phosphorylation by upstream receptor complexes, PLCG2 undergoes an activating conformational change and is recruited to the plasma membrane.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Magno L, Bunney TD, Mead E, Svensson F, Bictash MN. TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation. Mol Neurodegener. 2021; 16: 22. 33823896 PMC8022522 source

      The structural-perspective section says phosphorylation releases inhibitory interactions, supporting an activating conformational change. But the microglia-signalling section describes membrane recruitment followed by removal of autoinhibition, while the Fig. 1 caption says phosphorylation of membrane-localised adaptors recruits PLCγ2. The source therefore does not support the claim that phosphorylation of PLCG2 causes its recruitment to the plasma membrane. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] Siraliev‐Perez E, Stariha JTB, Hoffmann RM, et al. Dynamics of allosteric regulation of the phospholipase C‐gamma isozymes upon recruitment to membranes. Elife. 2022; 11: e77809. 35708309 PMC9203054 source

      The Introduction says PLC-γ2 requires Tyr759 phosphorylation for regulated activation, and the Discussion describes recruitment of PLC-γ isozymes to membrane-resident receptors as a step toward activation (pages not specified in our copy). But the paper's explicit sequence, described for PLC-γ1, places receptor-mediated recruitment before phosphorylation of the enzyme; it does not establish the claimed order for PLC-γ2. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Microglia dynamically interact with disease processes to influence AD progression.

    “Microglia, the innate immune cells of the brain, dynamically interact with these disease processes to influence AD progression.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Lee CYD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm. 2010; 117: 949‐ 60. 20552234 PMC3653296 source

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

    Premisecitation

    PLCG2 plays a critical role in transducing signals emanating from a number of immune receptors, acting as an intracellular hub for immune signaling.

    “PLCG2 plays a critical role in transducing signals emanating from a number of immune receptors, acting as an intracellular hub for immune signaling.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [15] Aki D, Minoda Y, Yoshida H, et al. Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells. Genes Cells. 2008; 13: 199‐ 208. 18233961 source
    • cites [16] Andreone BJ, Przybyla L, Llapashtica C, et al. Alzheimer's‐associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23: 927‐ 38. 32514138 source
    • cites [17] Hu X, Li S, Doycheva DM, et al. Rh‐CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE. J Neuroinflammation. 2020; 17: 182. 32522286 PMC7285566 source

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

    Premisecitation

    Mutations which alter PLCG2 function result in pleiotropic effects impacting immune, vascular, and nervous functions, as well as contributing to cancer pathogenesis and treatment resistance.

    “Genetic variants of PLCG2 are associated with altered risk for AD, and mutations which alter its function result in pleiotropic effects impacting immune, vascular, and nervous functions, as well as contributing to cancer pathogenesis and treatment resistance.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [10] Jackson JT, Mulazzani E, Nutt SL, Masters SL. The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration. J Biol Chem. 2021; 297: 100905. 34157287 PMC8318911 source

      The Conclusion and the sections on neurological diseases and cancer (pages unavailable) link PLCG2 variants or altered function to immune disorders, reduced Alzheimer’s disease risk, cancer, and ibrutinib-resistant leukemia. The autoimmune-disease section links common PLCG2 variants to venous thromboembolism, but does not establish that function-altering mutations cause vascular dysfunction; that part of the claim is more specific than the evidence. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [11] Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial‐mediated innate immunity in Alzheimer's disease. Nat Genet. 2017; 49: 1373‐ 84. 28714976 PMC5669039 source

      The PLCG2 discussion (indexed under Abstract; page not supplied) links function-altering variants to immune disorders and describes PLCG2 expression in brain microglia. The association results (also indexed under Abstract) link a PLCG2 variant to reduced late-onset Alzheimer’s disease risk. Our copy does not establish effects on vascular function or a contribution to cancer pathogenesis or treatment resistance. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    PLCG2 mediates transduction of many other cell surface receptors in addition to TREM2.

    “Likewise, PLCG2 mediates transduction of many other cell surface receptors in addition to TREM2. 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [13] Magno L, Bunney TD, Mead E, Svensson F, Bictash MN. TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation. Mol Neurodegener. 2021; 16: 22. 33823896 PMC8022522 source
    • cites [15] Aki D, Minoda Y, Yoshida H, et al. Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells. Genes Cells. 2008; 13: 199‐ 208. 18233961 source
    • cites [16] Andreone BJ, Przybyla L, Llapashtica C, et al. Alzheimer's‐associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23: 927‐ 38. 32514138 source

  • May combine two claims.

    Premisecitation

    The loss-of-function PLCG2M28L variant confers resistance to the Bruton Tyrosine Kinase inhibitor ibrutinib, worsens Aβ pathology, and increases risk of AD.

    “Conversely, the loss‐of‐function PLCG2M28L variant confers resistance to the Bruton Tyrosine Kinase inhibitor ibrutinib, worsens Aβ pathology, and increases risk of AD.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [27] Tsai AP, Dong C, Lin PB‐C, et al. Genetic variants of phospholipase C‐γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease. Immunity. 2023; 56: 2121‐ 2136.e6. 37659412 PMC10564391 source

      The Summary and Discussion describe PLCG2 M28L as loss-of-function and report increased amyloid plaque burden in an AD mouse model; the genetic analysis section associates it with elevated AD risk. The Introduction says M28L was found in patients with BTK inhibitor-resistant leukemia, but does not show that M28L itself confers resistance to ibrutinib. It attributes BTK inhibitor resistance to other PLCG2 mutations. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [28] Li K, Ran B, Wang Y, Liu L, Li W. PLCgamma2 impacts microglia‐related effectors revealing variants and pathways important in Alzheimer's disease. Front Cell Dev Biol. 2022; 10: 999061. 36147734 PMC9485805 source

      The section on the M28L variant (page unavailable) reports increased late-onset Alzheimer’s disease risk and resistance to a BTK inhibitor; the paper’s references identify ibrutinib as a BTK inhibitor. It does not establish that M28L is loss-of-function, and it explicitly says that M28L’s interaction with Aβ and other AD pathological markers had not been studied. The claim that it worsens Aβ pathology is therefore unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [29] Oblak AL, Kotredes KP, Pandey RS, et al. Plcg2M28L interacts with high fat/high sugar diet to accelerate Alzheimer's disease‐relevant phenotypes in mice. Front Aging Neurosci. 2022; 14: 886575. 35813947 PMC9263289 source

      The Introduction and Methods describe Plcg2M28L as an AD risk variant, but the Introduction says its precise effects have not been elucidated. The Discussion states that the studied mice lacked amyloid-beta plaques, rather than showing worsened Aβ pathology. No passage found in our copy supports loss of function or resistance to ibrutinib. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The intracellular signaling pathway downstream of TREM2 is complex and involves many molecules in addition to PLCG2, including Syk and PI3K.

    “The intracellular signaling pathway downstream TREM2 is complex and involves many molecules in addition to PLCG2, including Syk and PI3K. 32 , 33 , 35 , 43 , 58 , 59”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [32] Ennerfelt H, Frost EL, Shapiro DA, et al. SYK coordinates neuroprotective microglial responses in neurodegenerative disease. Cell. 2022; 185: 4135‐ 4152.e22. 36257314 PMC9617784 source

      The Introduction identifies SYK as a kinase downstream of TREM2, and the Results report that loss of SYK alters PI3K/AKT signaling in microglia. The paper does not establish PI3K as downstream of TREM2 specifically, and the passages found do not address PLCG2. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [33] Krasemann S, Madore C, Cialic R, et al. The TREM2‐APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017; 47: 566‐ 581.e9. 28930663 PMC5719893 source

      The Results section describes TREM2-dependent APOE signaling and changes in microglial gene expression, but does not identify the intracellular molecules in the claim. Searches of our copy for PLCG2, Syk, PI3K, and their expanded names found no passage establishing that they participate downstream of TREM2. Page numbers were not available in the indexed copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [35] Soni DM, Lin PB‐C, Lee‐Gosselin A, et al. Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy. Alzheimers Dement. 2024; 20: 4985‐ 4998. 38923171 PMC11247686 source

      The Introduction (page unavailable) says INPP5D modulates downstream signaling associated with TREM2 and other immune receptors. A title in the References (page unavailable) links TREM2-dependent signaling to PI3K. Our copy does not identify Syk or PLCG2 as components of that pathway, so it supports only part of the attributed claim. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TREM2 plays a key and enigmatic role in the progression of AD, acting to drive microglial phagocytosis, survival, lipid homeostasis, and metabolism.

    “TREM2 plays a key and enigmatic role in the progression of AD, acting to drive microglial phagocytosis, survival, lipid homeostasis, and metabolism.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [15] Aki D, Minoda Y, Yoshida H, et al. Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells. Genes Cells. 2008; 13: 199‐ 208. 18233961 source

      The Introduction and the passage headed Abstract (page not provided) discuss PLCγ2-dependent responses to bacterial ligands in macrophages and dendritic cells. Searches for TREM2 and for Alzheimer’s disease or microglia returned no passage addressing TREM2’s role in AD progression, phagocytosis, survival, lipid homeostasis, or metabolism. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [36] Cheng‐Hathaway PJ, Reed‐Geaghan EG, Jay TR, et al. The Trem2 R47H variant confers loss‐of‐function‐like phenotypes in Alzheimer's disease. Mol Neurodegener. 2018; 13: 29. 29859094 PMC5984804 source

      The Background links TREM2 to AD progression and myeloid-cell survival, and the Discussion describes a demonstrated role in phagocytosis in vitro. Our copy does not establish that TREM2 drives microglial lipid homeostasis or metabolism; a cited reference mentions lipid sensing, which is not the same claim. No page numbers are provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [37] Jay TR, von Saucken VE, Landreth GE. TREM2 in neurodegenerative diseases. Mol Neurodegener. 2017; 12: 56. 28768545 PMC5541421 source

      The sections on phagocytic function and myeloid-cell survival support TREM2’s roles in Aβ uptake and microglial survival, while the AD pathology section describes a complex, stage-dependent role in disease progression (page numbers unavailable). The “Other functions of TREM2” section links deficiency to altered lipid metabolism in a mouse demyelination model but treats a broader lipid-related role as a possibility; it does not establish that TREM2 drives microglial lipid homeostasis or metabolism in AD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TREM2 deletion reduces microglial survival and phagocytosis in vitro and impacts plaque pathology across disease progression in amyloidogenic mouse models.

    “TREM2 deletion reduces microglial survival and phagocytosis in vitro and impacts plaque pathology across disease progression in amyloidogenic mouse models.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [39] Keren‐Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017; 169: 1276‐ 90.e17. 28602351 source

      The Results and Discussion report that Trem2 deletion in 5XFAD mice prevents full activation of a microglial program that includes phagocytic-pathway genes. They do not report reduced microglial survival or directly test phagocytosis in vitro. The Discussion cites another study for a late-stage disease effect, but this paper does not establish effects on plaque pathology across disease progression. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [41] Yuan P, Condello C, Keene CD, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016; 90: 724‐ 39. 27196974 PMC4898967 source

      The Results section ('Microglia processes envelop individual fibrils in early filamentous plaques'; page unavailable) reports that Trem2-deficient AD-like mice had a higher proportion of filamentous plaques, supporting an effect on plaque pathology. The Introduction cites prior in-vitro evidence of disrupted Aβ phagocytosis, and the Discussion reports reduced phagocytosis with complete Trem2 loss in vivo, not an in-vitro test by this study. Our copy does not establish reduced microglial survival or effects measured across disease progression. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [42] Jay TR, Hirsch AM, Broihier ML, t al. Disease progression‐dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. J Neurosci. 2017; 37: 637‐ 47. 28100745 PMC5242410 source

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

    Premisecitation

    Previous studies have identified significantly reduced birth rates of mice deficient in PLCG2, with females being more significantly impacted.

    “Previous studies have also identified significantly reduced birth rates of mice deficient in PLCG2, with females being more significantly impacted.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Hopp SC, Rogers JG, Smith S, et al. Multi‐omics analyses reveal novel effects of PLCgamma2 deficiency in the mouse brain. bioRxiv. 2023. doi: 10.1101/2023.12.06.570499 source

      The Results section reports fewer Plcg2 knockout mice than expected surviving to weaning—14% of males and 6% of females—and infers that some died in utero. The Discussion likewise reports lower-than-expected knockout yields and higher female mortality. However, the cited passages do not establish a statistically significant reduction in birth rates or a statistically significant sex difference; much of the measured difference concerns survival to weaning, not birth alone. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Previously, PLCG2 expression was shown to be associated with Aβ plaque load and microglia markers AIF1 and TMEM119 in human brains.

    “Previously, PLCG2 expression was shown to be associated with Aβ plaque load and the microglia markers AIF1 and TMEM119 in human brains.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Tsai AP, Dong C, Lin PBC, et al. PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome Med. 2022; 14: 17. 35180881 PMC8857783 source

  • May combine two claims.

    Premisecitation

    Murine microglia lacking TREM2 have deficient responses to Aβ and impaired acquisition of the neuroprotective disease-associated microglia (DAM) phenotype.

    “Murine microglia lacking TREM2 have deficient responses to Aβ and impaired acquisition of the neuroprotective disease‐associated microglia (DAM) phenotype.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [39] Keren‐Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017; 169: 1276‐ 90.e17. 28602351 source
    • cites [41] Yuan P, Condello C, Keene CD, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016; 90: 724‐ 39. 27196974 PMC4898967 source

      The Results section reports that Trem2-deficient mouse microglia have impaired process polarization toward Aβ plaques and reduced plaque coverage, supporting a deficient response to Aβ. The paper describes this as a failure of the potentially neuroprotective microglial barrier; it does not establish impaired acquisition of a disease-associated microglia (DAM) phenotype. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [42] Jay TR, Hirsch AM, Broihier ML, t al. Disease progression‐dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. J Neurosci. 2017; 37: 637‐ 47. 28100745 PMC5242410 source

  • May combine two claims.

    Premisecitation

    The loss-of-function TREM2 variant R47H impairs microglial responses to Aβ and confers increased risk for AD.

    “Moreover, the loss‐of‐function TREM2 variant R47H impairs microglial responses to Aβ and confers increased risk for AD.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [36] Cheng‐Hathaway PJ, Reed‐Geaghan EG, Jay TR, et al. The Trem2 R47H variant confers loss‐of‐function‐like phenotypes in Alzheimer's disease. Mol Neurodegener. 2018; 13: 29. 29859094 PMC5984804 source
    • cites [38] Jonsson T, Jonsson PV, Levey AI, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013. PMC3677583 23150908 source

      The Results establish that R47H is associated with increased Alzheimer’s disease risk. The Discussion proposes that R47H may reduce TREM2 activity and impair microglial clearance of amyloid, but does not establish that R47H is a loss-of-function variant or that it impairs microglial responses to Aβ. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The GOF P522R variant of PLCG2 confers protection in AD and the M28L variant confers risk.

    “the GOF P522R variant of PLCG2 confers protection in AD and the M28L variant confers risk”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [11] Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial‐mediated innate immunity in Alzheimer's disease. Nat Genet. 2017; 49: 1373‐ 84. 28714976 PMC5669039 source

      The paper reports that PLCG2 p.P522R is associated with decreased late-onset Alzheimer’s disease risk (OR 0.68). It does not identify p.P522R as gain-of-function or report that PLCG2 M28L confers risk; its discussion of gain and loss of function concerns other PLCG2 mutations. No page number is available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [22] Claes C, England WE, Danhash EP, et al. The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model. Alzheimers Dement. 2022; 18: 1765‐ 78. 35142046 PMC9360195 source

      The Narrative states that P522R is associated with reduced risk of late-onset AD, and the Research in Context section describes its hypermorphic enzyme activity, supporting the protective gain-of-function portion. No passage found for M28L states that it confers AD risk; that portion of the claim is unsupported by our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] Diks AM, Teodosio C, de Mooij B, et al. Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system. Mol Neurodegener. 2023; 18: 25. 37081539 PMC10116473 source

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

    Interpretationcitation

    The reduced MOAB2+ plaque sizes may be a result of reduced oligomeric Aβ compaction.

    “which may be a result of reduced oligomeric Aβ compaction as described previously in another amyloidogenic mouse model. 62”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Meilandt WJ, Ngu H, Gogineni A, 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: 1956‐ 1974. 31980586 PMC7046459 source

      The Results section (page not available) suggests that Trem2 deficiency may reduce the incorporation and compaction of Aβ into existing plaques in PS2APP mice. The Discussion also links reduced compact-plaque accumulation with elevated soluble fibrillar Aβ oligomers. The paper does not examine MOAB2+ plaque sizes or specifically show that reduced compaction of oligomeric Aβ causes smaller plaques. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TREM2 loss-of-function impairs microglial protective functions and worsens neuronal dystrophy.

    “TREM2 loss‐of‐function impairs microglial protective functions and worsens neuronal dystrophy. 9 , 37 , 38 , 41 , 42 , 61”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [9] Karch CM, Goate AM. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015; 77: 43‐ 51. 24951455 PMC4234692 source

      The Immune Response > TREM2 section says TREM2 stimulates microglial phagocytosis and suppresses inflammation, supporting its protective role. It reports more extensive brain atrophy in TREM2 mutation carriers with Alzheimer’s disease, but does not establish that loss of function impairs those activities or worsens neuronal dystrophy specifically. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [37] Jay TR, von Saucken VE, Landreth GE. TREM2 in neurodegenerative diseases. Mol Neurodegener. 2017; 12: 56. 28768545 PMC5541421 source

      The section “TREM2 modulates neuritic dystrophy in AD” reports increased dystrophy around plaques in TREM2-deficient mice and human R47H carriers with AD. It also suggests that TREM2 enables microglial clustering that may form a protective barrier, but cautions that not all evidence supports a protective role. The claim presents that proposed protective function as established and does not limit the dystrophy finding to the AD plaque setting. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [38] Jonsson T, Jonsson PV, Levey AI, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013. PMC3677583 23150908 source

      The Discussion (page unavailable) reports that TREM2 knock-down reduces microglial phagocytosis of apoptotic neurons, supporting an impaired protective function. It does not report that TREM2 loss-of-function worsens neuronal dystrophy; its proposed link between reduced TREM2 activity and brain damage is explicitly tentative. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The loss-of-function PLCG2M28L variant reduces PLCG2 expression, exacerbates AD pathology, impairs microglial responsivity to Aβ, and disrupts microglial response gene expression.

    “Similar to total PLCG2 knockout, the loss‐of‐function PLCG2M28L variant reduces PLCG2 expression, exacerbates AD pathology, impairs microglial responsivity to Aβ, and disrupts microglial response gene expression. 27”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Tsai AP, Dong C, Lin PB‐C, et al. Genetic variants of phospholipase C‐γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease. Immunity. 2023; 56: 2121‐ 2136.e6. 37659412 PMC10564391 source

  • The quote only partly states this claim.

    Findingown data

    In cortices of 5xFADWT mice, PLCG2 protein expression assessed by immunohistochemistry and immunoblotting was unchanged compared to B6WT mice.

    “In the cortices of 5xFADWT mice, PLCG2 protein expression assessed by immunohistochemistry and immunoblotting was unchanged”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LAMP1-positive dystrophic neurite area normalized to the number of X34+ plaques was increased with TREM2 and PLCG2 deficiencies, although this was only significant in TREM2-deficient animals.

    “lysosomal‐associated membrane protein 1 (LAMP1)‐positive dystrophic neurite area normalized to the number of X34+ plaques was increased with TREM2 and PLCG2 deficiencies, although this was only significant in TREM2‐deficient animals”
    Quote in the paperSubstantial claim

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

    Findingown data

    The authors did not observe overt changes in expected litter sizes.

    “While we did not observe overt changes in expected litter sizes, it is unclear what might be driving the non‐Mendelian inheritance patterns of PLCG2‐deficient mice.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    There is a potential sex- and genotype-dependent effect on Il4ra isoform proportions.

    “we identified a potential sex‐ and genotype‐dependent effect on Il4ra isoform proportions, potentially indicating an effect on alternative splicing for this gene (Figure S5A–C in supporting information).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were 469 shared DEGs, 581 specific for 5xFAD Plcg2-/- mice, and 382 specific for 5xFAD Trem2-/- mice.

    “There were 469 shared DEGs, 581 specific for 5xFAD Plcg2‐/‐ mice, and 382 specific for 5xFAD Trem2‐/− mice (Figure 5B, Figure S4 in supporting information).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    PLCG2 and TREM2 deficiencies exhibited similar microglial phenotypes, amyloid plaque burden, and neuronal dystrophy.

    “PLCG2 and TREM2 deficiencies exhibited similar microglial phenotypes, amyloid plaque burden, and neuronal dystrophy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both PLCG2 and TREM2 deficiencies significantly reduced microglial coverage and engagement of plaques.

    “and significantly reduced microglial coverage and engagement of plaques.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In PLCG2-deficient B6 mice, TREM2 expression was reduced but did not reach significance.

    “Moreover, in PLCG2‐deficient B6 mice, TREM2 expression was reduced, but did not reach significance, potentially due to low expression of TREM2 in non‐diseased model mice.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    At the present time, only six 5xFAD;homozygous PLCG2 knockout mice (Plcg2−/−) have been acquired.

    “At the present time, we have only acquired six 5xFAD;homozygous PLCG2 knockout mice (Plcg2−/− ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Phagolysosomal processes rely only in part on TREM2 but more substantially on PLCG2, potentially through other receptors which depend on PLCG2-mediated signal transduction.

    “suggesting that phagolysosomal processes rely only in part on TREM2 but more substantially on PLCG2, potentially through other receptors which depend on PLCG2‐mediated signal transduction.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In different models of PLCG2 depletion, homozygous knockout embryos were found to have significant subcutaneous hemorrhaging, suggesting impacted vascular development and bleeding that may underlie embryonic death and reduced frequencies at weaning.

    “In different models of PLCG2 depletion, homozygous knockout embryos were found to have significant subcutaneous hemorrhaging, suggesting impacted vascular development and bleeding that may underlie embryonic death and reduced frequencies at weaning.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Wang D, Feng J, Wen R, et al. Phospholipase Cγ2 is essential in the functions of B cell and several Fc receptors. Immunity. 2000; 13: 25‐ 35. 10933392 source
    • cites [44] Ichise H, Ichise T, Ohtani O, Yoshida N. Phospholipase Cgamma2 is necessary for separation of blood and lymphatic vasculature in mice. Development. 2009; 136: 191‐ 5. 19056831 source

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

    Study design and conductown data

    Despite extensive breeding attempts of PLCG2+/- mice with 5xFAD+/- mice, the authors encountered difficulty generating 5xFAD mice with total PLCG2 deficiency.

    “Despite extensive breeding attempts of PLCG2+/− mice with 5xFAD+/− mice, we have encountered difficulty generating 5xFAD mice with total PLCG2 deficiency.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    TREM2 and PLCG2 deficiencies alter plaque development and compaction.

    “suggesting that TREM2 and PLCG2 deficiencies alter plaque development and compaction”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Sex-based batch effects were corrected for by omitting genes expressed on chromosomes X and Y.

    “Sex‐based batch effects were corrected for by omitting genes expressed on chromosomes X and Y.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Male and female mice were included in all experimental groups.

    “Male and female mice were included in all experimental groups.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    TREM2 immunohistochemistry was assessed qualitatively.

    “TREM2 immunohistochemistry was assessed qualitatively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PLCG2-deficient iMGs at baseline shared almost 50% of the DEGs identified in TREM2-deficient iMGs, and these genes were enriched in pathways associated with phagocytosis and DAP12 signaling.

    “PLCG2‐deficient iMGs at baseline shared almost 50% of the DEGs identified in TREM2‐deficient iMGs, and these genes were enriched in pathways associated with phagocytosis and DAP12 signaling, 16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Andreone BJ, Przybyla L, Llapashtica C, et al. Alzheimer's‐associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23: 927‐ 38. 32514138 source

  • May combine two claims.

    Interpretationown data

    PLCG2 may be critical for facilitating upregulation of TREM2 in response to Aβ in addition to mediating downstream transduction.

    “we show that PLCG2 may be critical for facilitating upregulation of TREM2 in response to Aβ in addition to mediating downstream transduction.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The role of PLCG2 in vital signal transduction pathways of microglial immune receptors, especially TREM2, remains unclear in the context of AD.

  • May combine two claims.

    Premisecitation

    The effects of TREM2 depletion depend on the stage of disease progression, ameliorating pathology early and exacerbating it later in the APP PS1-21 mouse model.

    “the effects of TREM2 depletion depend on the stage of disease progression, in which it ameliorates pathology early and exacerbates it later in the APP PS1‐21 mouse model. 42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Jay TR, Hirsch AM, Broihier ML, t al. Disease progression‐dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. J Neurosci. 2017; 37: 637‐ 47. 28100745 PMC5242410 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous work has shown that PLCG2 depletion inhibits TREM2 signaling in response to TREM2 ligands in vitro.

    “Previous work has shown that PLCG2 depletion inhibits TREM2 signaling in response to TREM2 ligands in vitro. 16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Andreone BJ, Przybyla L, Llapashtica C, et al. Alzheimer's‐associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23: 927‐ 38. 32514138 source

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

    Interpretationreasoning

    PLCG2 plays a role as a node of many different upstream signaling sources.

    “These genes and associated pathways reveal insights into which mechanisms might be uniquely disrupted in each condition and will help delineate the role that PLCG2 plays as a node of many different upstream signaling sources.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Bulk RNA-seq does not allow for the assessment of cell type-specific gene expression.

    “Of note, bulk RNA‐seq does not allow for the assessment of cell type–specific gene expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The discussed DEGs are predominantly expressed by microglia.
43 of 43

  • The paper relies on this without support.

    PLCG2 and TREM2 are predominantly expressed by microglia.

    “because both PLCG2 and TREM2 are predominantly expressed by microglia, we normalized their gene expression by AIF1 expression levels to account for differing levels of microgliosis”

  • The paper relies on this without support.

    AIF1 expression levels account for differing levels of microgliosis.

    “because both PLCG2 and TREM2 are predominantly expressed by microglia, we normalized their gene expression by AIF1 expression levels to account for differing levels of microgliosis”

  • The paper relies on this without support.

    The role of PLCG2 in vital signal transduction pathways of microglial immune receptors, especially TREM2, remains unclear in the context of AD.

    “The role of PLCG2 in vital signal transduction pathways of microglial immune receptors, especially TREM2, remains unclear in the context of AD.”

  • The paper relies on this without support.

    Previous research established the importance of PLCG2 downstream of TREM2.

    “While previous research established the importance of PLCG2 downstream of TREM2”

  • The paper relies on this without support.

    Bulk RNA-seq does not allow for the assessment of cell type-specific gene expression.

    “Of note, bulk RNA‐seq does not allow for the assessment of cell type–specific gene expression.”

  • The paper relies on this without support.

    The discussed DEGs are predominantly expressed by microglia.

    “Although the discussed DEGs are predominantly expressed by microglia”
6 of 6

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?

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.

  • Conflicting counts of shared DEGs

    Major

    The Results report 469 DEGs shared between the two knockout comparisons, whereas the Discussion reports 578 shared DEGs for those same comparisons.

  • Figure 5 caption reverses the shared and unshared panel labels

    Minor

    The Results assign shared DEG enrichment to Figure 5C and genotype-specific enrichment to Figures 5D and 5E. The figure caption instead labels E as shared and C and D as unshared.

2 of 2

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Authors
Messenger, E. J., Baar, S. A., Bedford, L. M., Tsai, A. P., Lin, P. B., Ferguson, C. A., Xu, G., Wallace, A., Landreth, G. E., Lamb, B. T., & Bissel, S. J.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
  • Lamb, Bruce T.
  • Bissel, Stephanie J.
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2025-05
Volume
21
Issue
5
Pages
e70231-e70231
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.70231
PMC
PMC12064341
OpenAlex
W4410219916
Semantic Scholar
0472f7b655f798163a0abab70bd59bb0638dfa1a
Cited by
16
References
61
Citations by year
2026: 13 · 2025: 3
FWCI
4.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
National Institute on Aging (RF1AG074566)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
PLCγ2, TREM2
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Male, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Signal Transduction, Amyloid beta-Peptides, Microglia, Mice, Knockout, Mice, Phospholipase C gamma, 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.

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Statistics and arithmetic are recomputed, not judged.

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