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Cited by 92Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

Open access
Tsai, Andy P., Dong, Chuanpeng, Lin, Peter Bor-Chian, Messenger, Evan J., Casali, Brad T., Moutinho, Miguel, Liu, Yunlong, Oblak, Adrian L. +4 more·2022·Genome Medicine
DOI 10.1186/s13073-022-01022-0PMC PMC8857783
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Abstract

Background: Alzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood. Methods: Using bulk RNA-Seq ( N =1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers ( AIF1 and TMEM119 ). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology. Results: We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide. Conclusions: Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.

AI snapshot

Written from the paper’s full text.

TL;DR

PLCG2 expression is upregulated in multiple LOAD brain regions and correlates with amyloid plaque density and microglial marker expression, with validation in 5xFAD mice showing plaque- and microglia-dependent Plcg2 induction. Differential expression and co-expression analyses link PLCG2 to inflammatory and NF-κB/lipopolysaccharide-related pathways in human and mouse microglia.

Key findings

  • PLCG2 was overexpressed in LOAD versus CN in temporal cortex (logFC=0.27, p=4.56E-02), parahippocampal gyrus (logFC=0.55, p=1.74E-03), superior temporal gyrus (logFC=0.46, p=2.55E-02), and inferior prefrontal gyrus (logFC=0.36, p=1.38E-02), but not in cerebellum, frontal pole, or dorsolateral prefrontal cortex.
  • PLCG2 expression was positively associated with amyloid plaque density in parahippocampal gyrus (β=0.027, p=5.22E-05), superior temporal gyrus (β=0.026, p=2.02E-04), and inferior prefrontal cortex (β=0.017, p=2.73E-03), but not frontal pole (β=0.01, p=0.08).
  • In 5xFAD mice, Plcg2 increased at 4 months (1.39-fold cortex, 1.37-fold hippocampus), 6 months (2.37-fold cortex, 1.96-fold hippocampus), and 8 months (2.43-fold cortex, 2.67-fold hippocampus); PLX5622 treatment abolished this increase despite only 70% microglial depletion, and expression was restored after returning to normal diet. No Plcg2 increase was observed in 12-month P301S tauopathy mice.
  • Differential expression comparing CN with high versus low PLCG2 identified 5047 significant genes (FDR-corrected p<0.05; 4566 downregulated, 481 upregulated) and inflammatory response GO terms (FDR-corrected p=5.77E-32); Plcg2-inactivated mice showed 74 differentially expressed genes on the NanoString neuroinflammation panel, with 17 genes changing in the same direction as in humans. Single-cell PLCG2 co-expression analysis of 413 top 20% upregulated genes identified pathways including response to lipopolysaccharide and regulation of I-kappaB kinase/NF-kappaB signaling.

Methods

  • Bulk RNA-Seq data (N=1249) from AMP-AD cohorts (Mayo, MSBB, ROS/MAP) across seven brain regions were analyzed with limma for diagnostic group differences, using age, sex, and APOE ε4 carrier status as covariates; linear regression tested associations of PLCG2 with amyloid plaque density and microglial markers AIF1 and TMEM119.
  • Microglial single-cell RNA-Seq from 12 donors (4 MCI, 8 AD) from ROS/MAP dorsolateral prefrontal cortex yielded 15,021 cells after QC; Seurat was used for clustering/UMAP and GENIE3 for PLCG2 co-expression network analysis.
  • Mouse studies used WT and 5xFAD mice at 1, 4, 6, and 8 months, PLX5622 microglial depletion, and Plcg2-inactivated mice; readouts included qPCR, NanoString neuroinflammation panel, and immunofluorescence for IBA1/P2RY12, with t tests for WT versus 5xFAD comparisons.

Limitations

  • The paper does not include an explicit limitations section.
  • Evident from the text: human findings are post-mortem bulk RNA-Seq associations, so causality and directionality between PLCG2 expression, amyloid plaques, and microglial markers cannot be established.
  • Evident from the text: validation relies on amyloid-focused 5xFAD and Plcg2-inactivated mouse models; the absence of Plcg2 increase in P301S tauopathy suggests the findings may be amyloid-specific, and PLX5622 achieved only about 70% microglial depletion.

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

Integrity signals

Registry

Crossref · 10.1186/s13073-022-01022-0

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 16 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    A hypermorphic variant in PLCG2, rs72824905, is protective against AD risk.

    “a hypermorphic variant in PLCG2, rs72824905, is protective against AD risk [9–11].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [9] Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, 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. source

      The paper reports that PLCG2 rs72824905/p.P522R is associated with decreased late-onset Alzheimer’s disease risk (Abstract; page unavailable). It does not establish that this particular variant is hypermorphic. Its discussion of mixed gain and loss of function concerns other PLCG2 variants. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] Magno L, Lessard CB, Martins M, Lang V, Cruz P, Asi Y, et al. Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res Ther. 2019;11:16. source

      The Results section reports that PLCG2 p.P522R has a small hypermorphic effect, and the Conclusion calls it an AD-protective variant. Our copy does not identify p.P522R as rs72824905, so it does not verify the specific identifier in the claim. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [11] Maguire E, Menzies GE, Phillips T, Sasner M, Williams HM, Czubala MA, et al. PIP2 depletion and altered endocytosis caused by expression of Alzheimer’s disease-protective variant PLCgamma2 R522. EMBO J. 2021;40:e105603. source
  • Findingown data

    Increased PLCG2 expression levels positively correlate with expression levels of microglial marker genes AIF1 and TMEM119 in LOAD patients.

    “Here, we report that PLCG2 expression is increased in several brain regions of LOAD patients and that increased PLCG2 expression levels positively correlate with both brain amyloid plaques and expression levels of microglial marker genes (AIF1 and TMEM119) (Fig. 6) [34–36].”
    • Also stated in: § Discussion · plain
      “Moreover, expression levels of PLCG2 were significantly associated with expression levels of microglia-specific marker genes (AIF1 and TMEM119), which we validated in 5xFAD mice, showing that increased Plcg2 expression was induced by amyloid plaques and the increase reverted to control levels after significantly reducing microglia with the colony-stimulating factor-1 antagonist PLX5622.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [34] Hopperton KE, Mohammad D, Trepanier MO, Giuliano V, Bazinet RP. Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review. Mol Psychiatry. 2018;23:177–98. source

      The Results section identifies Iba1 as a microglial marker, and the References list a study identifying TMEM119 as a marker of a subset of human microglia (page numbers unavailable in our copy). The review does not report a correlation between PLCG2 expression and either marker in LOAD patients; the citing sentence presents that correlation as the citing authors’ own finding. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [35] Kaiser T, Feng G. Tmem119-EGFP and Tmem119-CreERT2 Transgenic Mice for Labeling and Manipulating Microglia. eNeuro. 2019;6. source

      The ‘EGFP is faithfully expressed in microglia’ section identifies IBA1 and TMEM119 as microglial proteins and shows their presence in labeled mouse microglia. It does not report PLCG2 expression or test its correlation with either marker in LOAD patients; that correlation is presented in the citing sentence as the citing authors’ own finding. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [36] Satoh J, Kino Y, Asahina N, Takitani M, Miyoshi J, Ishida T, et al. TMEM119 marks a subset of microglia in the human brain. Neuropathology. 2016;36:39–49. source
  • Findingown data

    The findings in the human brain were validated by differential expression analyses between WT and Plcg2-inactivated mice.

    “The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model recapitulates aspects of AD amyloid pathology relevant to human LOAD.
  • Findingown data

    Of the differentially expressed genes, 17 genes (16 downregulated and 1 upregulated) had the same differentially expressed directions in both humans and mice.

    “Of these genes, 17 genes shown in the volcano plot (16 downregulated and 1 upregulated) were identified to have the same differentially expressed directions in both humans and mice (Fig. 4c).”
    Quote in the paperSubstantial claim
  • Findingown data

    PLCG2 expression is increased in several brain regions of LOAD patients.

    “Here, we report that PLCG2 expression is increased in several brain regions of LOAD patients and that increased PLCG2 expression levels positively correlate with both brain amyloid plaques and expression levels of microglial marker genes (AIF1 and TMEM119) (Fig. 6) [34–36].”
    • Also stated in: § Conclusions · plain
      “In conclusion, PLCG2 expression is increased in several brain regions in LOAD patients and significantly correlates with brain amyloid burden in LOAD patients and AD model mice.”
    Quote in the paperSubstantial claim
  • May combine two claims. 9
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingcitation

    Our findings in humans were validated in mice with inactivated Plcg2 expression, which reduced expression levels of AD-associated microglial genes including CLEC7A, C3, and PIK3R5, in comparison with WT mice.

    “Our findings in humans were validated in mice with inactivated Plcg2 expression (PLCG2 inact), which reduced expression levels of AD-associated microglial genes [39, 40], including CLEC7A, C3, and PIK3R5, in comparison with expression levels of these genes in WT mice.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [39] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47(566-581):e569. source

      The Results section on MGnD microglia in the AD cortex identifies CLEC7A-positive microglia near amyloid plaques, supporting CLEC7A as an AD-associated microglial marker. It does not identify C3 or PIK3R5 in that association. Its reported reductions in CLEC7A concern Trem2 or Apoe deletion, not Plcg2 inactivation; the sentence presents the Plcg2 comparison as the citing authors’ own finding. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [40] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169:1276–1290.e1217. source

      The Results identify Clec7a as a marker of disease-associated microglia in AD-model mice, supporting that part of the cited gene classification. The passages do not identify C3 or PIK3R5 as such markers. The Plcg2-inactivation comparison is presented as the citing authors’ own finding, not as a result attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In AD, the effect of PLCG2 might depend on the stage of neurodegeneration, the gene expression, the enzymatic activity, and the formation of intracellular signaling complexes in microglia.

    “In AD, the effect of PLCG2 might depend on the stage of neurodegeneration, the gene expression, the enzymatic activity, and the formation of intracellular signaling complexes in microglia [10, 13–16].”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [10] Magno L, Lessard CB, Martins M, Lang V, Cruz P, Asi Y, et al. Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res Ther. 2019;11:16. source

      The Results section, “PLCG2 in microglia in Alzheimer’s disease” (page not provided), examines PLCG2 expression in plaque-associated microglia; the Conclusion (page not provided) reports increased activity of the protective variant. These findings support the expression and enzymatic-activity aspects, but the paper does not establish that PLCG2’s effect depends on the stage of neurodegeneration or on the formation of intracellular signaling complexes. The Discussion describes signaling links as possibilities for further study. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [13] Takalo M, Wittrahm R, Wefers B, Parhizkar S, Jokivarsi K, Kuulasmaa T, et al. The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions. Mol Neurodegener. 2020;15:52. source

      The Findings sections (page unavailable) report that the protective P522R variant alters brain gene-expression patterns and increases PLCγ2 enzyme activity in mouse macrophages, with evidence of altered microglial activation. They do not establish that PLCG2’s effect in AD depends on the stage of neurodegeneration or on the formation of intracellular signaling complexes in microglia; the authors say studies with AD-associated pathology are still needed. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [14] Hajicek N, Keith NC, Siraliev-Perez E, Temple BR, Huang W, Zhang Q, Harden TK, Sondek J. Structural basis for the activation of PLC-gamma isozymes by phosphorylation and cancer-associated mutations. Elife. 2019;8. source

      The Introduction links a moderately active PLC-γ2 variant to protection from late-onset Alzheimer’s disease, supporting a possible role for enzymatic activity. It also describes PLC-γ domains that scaffold signaling proteins, but neither the Introduction nor the Discussion says that PLCG2’s effect in Alzheimer’s depends on neurodegeneration stage, gene expression, or signaling-complex formation in microglia. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [15] Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, 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. source
    • cites [16] 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. source

      The sections on AD-associated variants and microglial signalling link PLCγ2 enzymatic activity and recruitment into signalling networks to microglial function. The therapy section raises the possibility that the benefit of TREM2/PLCγ2 pathway activation varies across disease progression, but its AD expression finding concerns TREM2, not PLCG2. The paper therefore does not establish the full set of proposed dependencies for PLCG2 itself. These passages have no page numbers in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Approximately 40% of the susceptibility genes identified in genetic studies of LOAD are immune- and microglia-related, suggesting that microglia are involved in modulating AD pathology.

    “approximately 40% of the susceptibility genes identified in genetic studies of LOAD are immune- and microglia-related, suggesting that microglia are involved in modulating AD pathology [8].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43–51. source

      The Immune Response section lists several LOAD risk genes involved in immune pathways, and its CD33 subsection describes microglial involvement in Aβ clearance and plaque burden. Our copy does not state or substantiate the claimed approximately 40% proportion of susceptibility genes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    PLCG2 expression significantly correlates with brain amyloid burden in LOAD patients and AD model mice.

    “In conclusion, PLCG2 expression is increased in several brain regions in LOAD patients and significantly correlates with brain amyloid burden in LOAD patients and AD model mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These genes and pathways are related to the inflammatory response, cytokine-mediated signaling, regulation of complement activation, chemotaxis, response to lipopolysaccharide, regulation of I-kappaB/NF-kappaB signaling, and response to interleukin-1.

    “These genes and pathways are related to the inflammatory response, cytokine-mediated signaling, regulation of complement activation, chemotaxis, response to lipopolysaccharide, regulation of I-kappaB/NF-kappaB signaling, and response to interleukin-1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the 5xFAD mouse model, Plcg2 expression increases in a disease progression-dependent manner and is associated with amyloid pathology.

    “These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology.”
    • Also stated in: § Background · plain
      “Similarly, in a 5xFAD mouse model, Plcg2 expression increased in a disease progression-dependent manner and Plcg2 was highly expressed in plaque-induced microglia in the brain.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model recapitulates aspects of AD amyloid pathology relevant to human LOAD.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Age, sex, and APOE ε4 carrier status were used as covariates in the differential expression analysis of PLCG2 among CN, MCI, and LOAD.

    “Age, sex, and APOE ε4 carrier status were used as covariates.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Both male and female mice were used, and the numbers of male and female mice were equally distributed.

    “Both male and female mice were used, and the numbers of male and female mice were equally distributed.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Experiments at the 2-, 4-, 6-, and 8-month time points were performed independently.

    “Experiments at the 2-, 4-, 6- and 8-month time points were performed independently”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    PLCG2 is a membrane-associated enzyme that catalyzes the conversion of PIP2 to IP3 and DAG, which plays a crucial role in cell-surface receptor signal transduction.

    “PLCG2 is a membrane-associated enzyme that catalyzes the conversion of phospholipid PIP2 (1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate) to IP3 (1D-myo-inositol 1,4,5-trisphosphate) and DAG (diacylglycerol), which plays a crucial role in cell-surface receptor signal transduction [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Hernandez D, Egan SE, Yulug IG, Fisher EM. Mapping the gene that encodes phosphatidylinositol-specific phospholipase C-gamma 2 in the human and the mouse. Genomics. 1994;23:504–7. source

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

    Study design and conductnone given

    Images were blinded for microglia morphology measurement.

    “Images were blinded, and the area coverage of microglia was calculated using ImageJ software [31].”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Increased Plcg2 expression was induced by amyloid plaques and the increase reverted to control levels after significantly reducing microglia with PLX5622.

    “Moreover, expression levels of PLCG2 were significantly associated with expression levels of microglia-specific marker genes (AIF1 and TMEM119), which we validated in 5xFAD mice, showing that increased Plcg2 expression was induced by amyloid plaques and the increase reverted to control levels after significantly reducing microglia with the colony-stimulating factor-1 antagonist PLX5622.”
    Quote in the paperSubstantial claim
12 of 12

  • The authors state this as an assumption.

    The role of PLCG2 in AD is poorly understood and has not been comprehensively explored.

    “However, the role of PLCG2 in AD is still poorly understood.”
    “However, the role of PLCG2 has not yet been comprehensively explored.”

  • The paper relies on this without support.

    The 5xFAD mouse model recapitulates aspects of AD amyloid pathology relevant to human LOAD.

    “These findings in the human brain were validated in the 5xFAD amyloid mouse model”
    “Similarly, in a 5xFAD mouse model, Plcg2 expression increased in a disease progression-dependent manner”

  • The paper relies on this without support.

    The 12-month P301S tauopathy mouse model exhibits robust microgliosis.

    “However, we did not observe any increase in Plcg2 expression in a 12-month tauopathy mouse model (P301S), which exhibits robust microgliosis (Additional file 2: Fig. S1).”
    “Interestingly, we did not observe an increase in Plcg2 expression in a 12-month tauopathy mouse model (P301S), which exhibits robust microgliosis, suggesting that the increase of Plcg2 might result from an association between microglia and amyloid plaques, rather than microgliosis.”

  • The paper relies on this without support.

    The ROS/MAP cohort cognitively normal participants selected by PLCG2 expression percentiles are representative of cognitively normal older adults.

    “We performed differential expression analysis of bulk RNA-Seq data from the ROS/MAP cohort by comparing CN in the 25th percentile of PLCG2 gene expression levels with CN participants in the 75th percentile of PLCG2 gene expression levels (Additional file 1: Table S3).”
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?

  • 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”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [12]

    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

  • PLCG2 encodes an enzyme predominately expressed in microglia within the central nervous system.

    “PLCG2 encodes an enzyme predominately expressed in microglia within the central nervous system. 11 , 12”

    From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [12]

    The Background identifies PLCG2 as a membrane-associated enzyme, and the Results report its expression in brain microglia. The Results finding that expression increased exclusively in microglia concerns 5xFAD mice with amyloid pathology; it does not establish that PLCG2 is predominantly expressed in microglia throughout the central nervous system. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • PLCG2 expression is associated with both amyloid and tau pathology.

    “PLCG2 expression has also been associated with both amyloid and tau pathology (4, 11).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [11]

    The Results section ('Increased PLCG2 expression levels are associated with amyloid plaques in the human brain'; page not provided) reports an association between PLCG2 expression and amyloid plaque density in three brain regions. It does not establish an association with tau pathology; the Discussion (page not provided) instead reports no increase in Plcg2 expression in a tauopathy mouse model. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • 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.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [12]

    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

  • Studies of PLCG2 haploinsufficiency in mice have revealed that reduced PLCG2 expression impairs expression of inflammation-associated genes.

    “Similarly, studies of PLCG2 haploinsufficiency in mice have revealed that reduced PLCG2 expression impairs expression of inflammation‐associated genes.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [12]

    The Results (Fig. 4) report that Plcg2-inactivated mice had 39 downregulated genes compared with wild-type mice, and the Discussion identifies reduced expression of AD-associated microglial genes. But the Methods describe a knockout mutation, not a haploinsufficiency model; our copy does not establish that the mice had only one functional Plcg2 copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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.

  • Mouse time-point lists disagree

    Minor

    The mice methods list a 1-month time point, whereas the statistical analysis lists a 2-month time point instead.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, et al. Alzheimer's-associated PLCgamma2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020;23:927–38. · DOI · Paper page
  2. Tsai AP, Dong C, Lin PB, Messenger EJ, Casali BT, Moutinho M, Liu Y, Oblak AL, Lamb BT, Landreth GE, Bissel SJ, Nho K, et al. PLCG2 is Associated with the Inflammatory Response and is Induced by Amyloid Plaques in Alzheimer's Disease. BioProject, PRJNA801624, NCBI Sequence Read Archive 2022. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195650.

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Authors
Tsai, A. P., Dong, C., Lin, P. B.-C., Messenger, E. J., Casali, B. T., Moutinho, M., Liu, Y., Oblak, A. L., Lamb, B. T., Landreth, G. E., Bissel, S. J., & Nho, K.
Affiliations
  • Indiana University School of Medicine
  • Indiana University Indianapolis (US)
Corresponding author
  • Bissel, Stephanie J.
  • Nho, Kwangsik
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-02-18
Volume
14
Issue
1
Pages
17-17
ISSN
1756-994X (ISSN-L)
DOI
10.1186/s13073-022-01022-0
PMC
PMC8857783
OpenAlex
W4213162357
Cited by
92
References
42
Citations by year
2026: 8 · 2025: 24 · 2024: 29 · 2023: 22 · 2022: 9
FWCI
10.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome Medicine (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (RF1 AG051495, RF1 AG050597, U54 AG054345, K01 AG054753, R03 AG063250, RF1 AG074566)
  • National Center for Advancing Translational Sciences (UL1TR002529)
  • U.S. National Library of Medicine (R01 LM012535)
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
PLCγ2, Alzheimer's disease, amyloid plaques, microglial activation, microglia, neuroinflammation, 5xFAD mice, NF-κB signaling, lipopolysaccharide response, AIF1, TMEM119, gene expression, single-cell RNA sequencing, co-expression network analysis, late-onset Alzheimer's disease
MeSH terms
Aged, Alzheimer Disease, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Microglia, 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.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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

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