The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions
Open accessAbstract
Background: Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods: To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results: Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. Conclusion: The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.
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Written from the paper’s full text.
TL;DR
The AD-associated protective PLCG2 P522R variant was modeled as a Plcγ2-P522R knock-in mouse and shown to mildly hyperactivate Plcγ2, enhancing macrophage survival, inflammatory cytokine release, and phagocytic capacity while increasing in vivo microglial activation markers without changing microglial number or morphology. The findings support TREM2–PLCγ2 pathway stimulation as a potential AD therapeutic direction.
Key findings
- Plcγ2-P522R KI mice were viable, fertile, and had no obvious detrimental phenotypes. KI BMDMs showed significantly higher basal Ip1 levels than WT (p < 0.001), enhanced survival after m-CSF withdrawal (LDH, *p < 0.05, p < 0.01), and reduced Caspase-3/7 activation.
- Phagocytosis was ~45% higher in KI BMDMs versus WT but not statistically significant. BV2 cells overexpressing human PLCγ2-P522R showed >2-fold higher phagocytic activity than PLCγ2-WT or control cells, while the overall number of phagocytic cells was only 11% and 15% higher upon PLCγ2-WT and PLCγ2-P522R overexpression, respectively.
- After LPS/IFNγ treatment, KI BMDMs released significantly higher TNFα, IL-6, and IL-1β, but significantly lower NO. Brain mRNA analysis found 57/770 (7%) genes significantly upregulated and 32/770 (4%) downregulated in KI versus WT mice; P2ry12 was significantly higher in KI cortex, and Gfap was increased with hypertrophic astrocytes in KI hippocampus.
- In one-year-old female mice, 18F-FEPPA PET signal was significantly increased in all analyzed brain areas of KI versus WT mice, while 18F-FDG uptake showed no significant differences. Immunohistochemistry did not reveal changes in microglia number or morphology.
Methods
- A Plcγ2-P522R knock-in mouse was generated using CRISPR/Cas9 gene editing; homozygous KI mice and WT littermates were used. BMDMs were prepared from six-month-old KI male mice and WT littermates, and BV2 microglia-like cells were transfected with human PLCγ2-WT, PLCγ2-P522R, or control vector.
- Assays included Ip1 ELISA, LDH cytotoxicity, Caspase-3/7 activation, phagocytosis assays, TNFα/IL-6/IL-1β ELISA, NO assay, NanoString neuropathology gene expression panel (770 genes), RT-qPCR, immunoblotting, immunofluorescence, and PET imaging with 18F-FEPPA and 18F-FDG in one-year-old female mice.
- Statistical analyses used independent samples t-test or Mann-Whitney U test, and two-way ANOVA with LSD post hoc test where appropriate; significance threshold was p < 0.05. NanoString data were analyzed with nSolver Advanced analysis software.
Limitations
- Stated by the paper: KI BMDM phagocytosis was not statistically significant; further functional studies on endosomal/lysosomal compartments in KI microglia are warranted; the cell-type origin of brain mRNA changes cannot be confirmed; firm conclusions on DAM phenotype require isolated microglia from aged KI mice with AD-associated pathology; and future studies are needed on microglia-mediated synaptic engulfment and neural network integrity.
- Evident from the text: several analyses used small samples (n = 3–4 per genotype; NanoString n = 3 per genotype; PET n = 3–4), no AD pathology model was used, BV2 overexpression does not fully model endogenous microglia, BMDM/brain mRNA analyses used male mice while PET used female mice, and no human validation is reported.
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Claims the paper makes
3 of 7 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Premisecitation
A rare coding variant in PLCG2 (rs72824905, p.P522R) expressed in myeloid lineage cells reduces the risk for Alzheimer's disease.
“A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] 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
- Interpretationreasoning
The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice support the notion to therapeutically stimulate TREM2 functions.
“The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice also support the notion to therapeutically stimulate TREM2 functions [6, 16, 17, 43].”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [6] Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J, Mei Y, Astarita G, Di Paolo G, Sandmann T, Monroe KM, Lewcock JW. Alzheimer's-associated PLCγ2 Is a Signaling Node Required for Both TREM2 Function and the Inflammatory Response in Human Microglia. Nat Neurosci. 2020. https://doi.org/10.1038/s41593-020-0650-6. source
- cites [16] Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G, Pettkus N, Brunner B, Sülzen A, Nuscher B, Hampel H, Xiang X, Feederle R, Tahirovic S, Park JI, Prorok R, Mahon C, Liang C, Shi J, Kim DJ, Sabelström H, Huang F, Di Paolo G, Simons M, Lewcock JW, Haass C. Enhancing Protective Microglial Activities With a Dual Function TREM2 Antibody to the Stalk Region. EMBO Mol Med. 2020;12:e11227. https://doi.org/10.15252/emmm.201911227. source
- cites [17] Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, Colonna M. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020;217(9):e20200785. https://doi.org/10.1084/jem.20200785. source
The Discussion (page unavailable) reports that activating human TREM2 with AL002c reduced pathology in an Alzheimer’s mouse model and describes anti-TREM2 antibodies as promising therapeutic candidates. The paper does not report the opposite phenotypes of PLCG2-knockout iMGs and Plcγ2-P522R knock-in mice, so it supports the therapeutic-TREM2 notion but not that stated basis for it. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [43] Deczkowska A, Weiner A, Amit I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020;181(6):1207–17. source
- Findingown data
Basal levels of Ip1 are significantly higher in cultured KI BMDM cells than in WT cells.
“Accordingly, significantly higher basal levels of Ip1 were detected in cultured KI BMDM cells as compared to WT cells (Fig. 1c)”
Quote in the paperSubstantial claim - Findingown data
Levels of P2ry12 are significantly higher in the cortex of KI mice compared to WT mice.
“The levels of a microglia-specific purinergic receptor P2ry12 were significantly higher in the cortex of KI mice as compared to WT mice (Fig. 2e)”
Quote in the paperSubstantial claim - Findingown data
Survival of KI BMDMs is enhanced compared to WT BMDMs after withdrawal of m-CSF.
“the survival of the KI BMDMs was enhanced as compared to WT BDMDs after withdrawal of macrophage colony stimulation factor (m-CSF) (Fig. 1d).”
Quote in the paperSubstantial claim
- Findingown data
Immunohistochemical analysis of Iba1 did not show significant alterations in microglia number or morphology in the brain of KI mice compared to WT mice.
“Immunohistochemical analysis of the microglia marker Iba1 did not show significant alterations in microglia number or morphology in the brain of KI mice as compared to WT mice (Fig. 2e).”
Quote in the paperSubstantial claim - Findingown data
Activity-related phosphorylation of Akt1/2 (S473/474) is significantly reduced in the brain of KI mice.
“However, activity-related phosphorylation of Akt1/2 (S473/474) was significantly reduced in the brain of KI mice (Fig. 2c).”
Quote in the paperSubstantial claim - Findingown data
More than two-fold higher phagocytic activity is detected in BV2 cells overexpressing PLCγ2-P522R compared to those expressing PLCγ2-WT or control plasmid.
“More than two-fold higher phagocytic activity was detected in BV2 cells overexpressing the PLCγ2-P522R variant as compared to those expressing PLCγ2-WT or a control plasmid (Fig. 1f).”
Quote in the paperSubstantial claim - Findingown data
Apoe is significantly upregulated in the brain of KI mice.
“a significant upregulation of Apoe, one of the key upregulated DAM genes [31, 37, 39], was detected in the brain of KI mice (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
A significant increase in 18F-FEPPA signal is detected in one-year-old KI mice compared to WT female mice in all analyzed brain areas.
“A significant increase in 18F-FEPPA signal was detected in one-year-old KI mice compared to WT female mice in all analyzed brain areas (Fig. 3a)”
Quote in the paperSubstantial claim - Findingown data
Significantly lower levels of nitric oxide are detected in the culture medium of KI BMDMs despite higher cytokine secretion.
“Despite higher cytokine secretion, significantly lower levels of nitric oxide (NO) were detected in the culture medium of KI BMDMs.”
Quote in the paperSubstantial claim - Findingown data
BMDMs from KI mice release significantly higher levels of TNFα, IL-6, and IL-1β into the culture medium upon LPS and IFNγ treatment.
“BMDMs from KI mice released significantly higher levels of tumor necrosis factor-α, (TNFα), interleukin-6 (IL-6), and -1β (IL-1β) into the culture medium (Fig. 1g)”
Quote in the paperSubstantial claim - Findingown data
Activation of Caspase-3/7 is significantly reduced in KI BMDMs.
“a significant reduction in the activation of Caspase-3/7 was detected in KI BMDMs (Fig. S2B)”
Quote in the paperSubstantial claim - Findingown data
Pathway analysis of RNA data suggests higher microglia activation in the brain of KI compared to WT mice.
“Pathway analysis of the RNA data suggested higher microglia activation in the brain of KI as compared to the WT mice (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Several genes directly linked to Plcγ2 signaling show significantly elevated expression in the KI mouse brain.
“Notably, several genes directly linked to Plcγ2 signaling (e.g. Itpr1, Camk2d, Mapk3/Erk1, Rac1, and Rhoa) showed a significantly elevated expression in the KI mouse brain (Fig. S3B).”
Quote in the paperSubstantial claim - Premisecitation
Loss of PLCγ2 function reduces TREM2-dependent support of cell survival, phagocytosis, and lipid metabolism.
“Loss of PLCγ2 function consequently reduces TREM2-dependent support of cell survival, phagocytosis and lipid metabolism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J, Mei Y, Astarita G, Di Paolo G, Sandmann T, Monroe KM, Lewcock JW. Alzheimer's-associated PLCγ2 Is a Signaling Node Required for Both TREM2 Function and the Inflammatory Response in Human Microglia. Nat Neurosci. 2020. https://doi.org/10.1038/s41593-020-0650-6. source
- Interpretationreasoning
The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling.
“The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling.”
Quote in the paperSubstantial claim - Interpretationown data
The Plcγ2-P522R variant moderately increases at least a subset of DAM-associated signature genes.
“Taken together, the Plcγ2-P522R variant moderately increases at least a subset of DAM-associated signature genes.”
Quote in the paperSubstantial claim - Interpretationown data
The protective Plcγ2-P522R variant promotes a subset of reactive astrocytes in the KI mouse hippocampus.
“These results suggest that the presence of the protective Plcγ2-P522R variant promotes a subset of reactive astrocytes in the KI mouse hippocampus.”
Quote in the paperSubstantial claim - Interpretationreasoning
Trem2 and Plcγ2 act on the same pathway.
“This further supports the notion that Trem2 and Plcγ2 act on the same pathway (Fig. 1a) [6]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J, Mei Y, Astarita G, Di Paolo G, Sandmann T, Monroe KM, Lewcock JW. Alzheimer's-associated PLCγ2 Is a Signaling Node Required for Both TREM2 Function and the Inflammatory Response in Human Microglia. Nat Neurosci. 2020. https://doi.org/10.1038/s41593-020-0650-6. source
- Interpretationown data
The P522R variant protects BMDMs from apoptosis.
“suggesting that the P522R variant protects BMDMs from apoptosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
The P522R variant protects cells under different stress conditions.
“Thus, our observation supports the idea that the P522R variant protects cells under different stress conditions.”
Quote in the paperSubstantial claim - Interpretationreasoning
The reduced Akt phosphorylation supports the notion that KI mice use more Pip2 as substrate to produce Dag and Ip3 and consequently less Pip3 exists for Akt1/2 activation.
“Therefore, this finding supports the notion that KI mice use more Pip2 as a substrate to produce Dag and Ip3 and consequently, less Pip3 exists for the activation of Akt1/2 (Fig. 2d).”
Quote in the paperSubstantial claim - Interpretationown data
The relatively mild microglia activation in the presence of the Plcγ2-P522R variant is not detrimental.
“suggesting that the relatively mild microglia activation in the presence of the Plcγ2-P522R variant is not detrimental.”
Quote in the paperSubstantial claim - Interpretationown data
The P522R variant exerts a mild hypermorphic effect on the basal enzyme activity of Plcγ2 in cultured mouse BMDMs.
“suggesting that the P522R variant exerts a mild hypermorphic effect on the basal enzyme activity of Plcγ2 in the cultured mouse BMDMs.”
Quote in the paperSubstantial claim - Interpretationreasoning
Pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for Alzheimer's disease.
“Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.”
Quote in the paperSubstantial claim - Interpretationown data
RNA and immunohistochemistry data suggest the P522R variant promotes expressional changes linked to altered activation status of microglia, which are not explained by increased microglia number.
“Collectively, our RNA and immunohistochemistry data suggest that the P522R variant promotes expressional changes linked to the altered activation status of microglia, which are not explained by the increased number of microglia.”
Quote in the paperSubstantial claim - Interpretationown data
The P522R variant increases phagocytic capacity per cell.
“suggesting an increased phagocytic capacity per cell.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 9
May combine two claims.
Findingown dataHomozygous Plcγ2-P522R knock-in mice are viable, fertile, and do not show obvious detrimental phenotypes.
“Homozygous mice were viable, fertile, and did not show obvious detrimental phenotypes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOut of 770 analyzed genes, 57 (7%) were significantly up- and 32 (4%) significantly downregulated in the brain of KI compared to WT mice.
“Out of 770 analyzed genes, 57 (7%) were significantly up- and 32 (4%) significantly downregulated in the brain of KI as compared to WT mice (Fig. 2a, b, Fig. S3A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExpression of the astrocytic marker Gfap is increased in the KI mouse brain, and immunohistochemical analysis reveals stronger Gfap staining and hypertrophic astrocyte morphology in the hippocampus of KI compared to WT mice.
“Additionally, expression of the astrocytic marker, Gfap, was increased in the KI mouse brain (Fig. 2a).”
- Also stated in: § The mRNA profile associated with Plcγ2-P522R indicates microglia activation and the modulation of Plcγ2 signaling · plain
“Accordingly, immunohistochemical analysis revealed a significantly stronger staining of Gfap and a hypertrophic morphology of astrocytes in the hippocampus of KI as compared to WT mice (Fig. 2c).”
Quote in the paperNot a substantial claim- Also stated in: § The mRNA profile associated with Plcγ2-P522R indicates microglia activation and the modulation of Plcγ2 signaling · plain
May combine two claims.
Findingown dataCerebral glucose uptake as detected by 18F-FDG-PET shows no significant differences in any brain region and no correlation between 18F-FEPPA and 18F-FDG signals in KI mouse brain.
“The cerebral uptake of glucose as detected by 18F-FDG-PET [42] did not show significant differences in glucose uptake in any of the brain regions studied nor any correlation between 18F-FEPPA and 18F-FDG signals in KI mouse brain”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenPET data were gathered in list-mode form and corrected for dead-time, randoms, scatter and attenuation.
“Data were gathered in list-mode form, and corrected for dead-time, randoms, scatter and attenuation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenGene expression data were analyzed using nSolver Advanced analysis software with built-in quality control, normalization, and statistical analyses.
“Gene expression data were analyzed using nSolver Advanced analysis software (NanoString Technologies) with build-in quality control, normalization, and statistical analyses.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe integrity of the insert sequence and the introduction of the point mutation in the PLCγ2-P522R-myc-DDK construct were confirmed by Sanger sequencing of the isolated plasmid DNA.
“Integrity of the insert sequence and introduction of the point mutation were confirmed by Sanger sequencing of the isolated plasmid DNA.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenImmunohistochemical data were checked for normality using the Shapiro-Wilk method, the D'Agostino and Pearson, as well as the Kolmogorov-Smirnov normality tests.
“Immunohistochemical data were checked for normality using the Shapiro-Wilk method, the D’Agostino and Pearson, as well as the Kolmogrov-Smirnov normality tests.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe protective P522R variant sensitizes myeloid cells and potentially allows a more effective response upon neurodegeneration.
“Therefore, our findings suggest that the protective P522R variant sensitizes myeloid cells and potentially allows a more effective response upon neurodegeneration.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe protective Plcγ2-P522R variant potentiates the primary function of Plcγ2 and promotes important immune cell functions in vitro.
“In conclusion, our results suggest that the protective Plcγ2-P522R variant potentiates the primary function of Plcγ2 and thus, promotes important immune cell functions in vitro.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRNA concentration and quality were determined using the Agilent RNA 6000 Nano Kit according to the manufacturer's recommendations.
“RNA concentration and quality were determined using Agilent RNA 6000 Nano Kit according to the manufacturer’s recommendations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn the BMDM phagocytosis assay, the assay was repeated in two independent experiments.
“The assay was repeated in two independent experiments.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenStatistical significance between groups was tested using independent samples t-test or Mann-Whitney U test depending on whether the data fulfilled the assumptions for parametric tests, or with two-way ANOVA followed by LSD post-hoc test for more than two groups.
“Statistical significance between groups was tested using independent samples t-test or Mann-Whitney U test depending whether the data fulfilled the assumptions for parametric tests or with two-way ANOVA (more than two groups) followed by LSD post-hoc test.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPlcγ2-P522R also promotes microglia activation in vivo, without affecting the total number or morphology of microglia.
“Based on the RNA, immunohistochemistry, and PET imaging data, Plcγ2-P522R also promotes microglia activation in vivo, without affecting the total number or morphology of microglia.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataIn the BV2 cell phagocytosis assay, non-viable cells were excluded by staining with 7-AAD, and pHrodo fluorescent signal was analyzed from 20,000 live cells by flow cytometry.
“Non-viable cells were excluded by staining with 7-AAD Staining Solution (Abcam) for 5 min and pHrodo fluorescent signal was analyzed from 20,000 live cells by flow cytometry.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLaser and detector settings were maintained constant for the acquisition of each immunostaining.
“Laser and detector settings were maintained constant for the acquisition of each immunostaining.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Whether the P522R variant affects microglial and other myeloid lineage cell functions was not known.
“The P522R variation locates in the regulatory domain of Plcγ2, but whether this variant affects the above-mentioned functions of microglia and other myeloid lineage cells, is not known.”
The paper relies on this without support.
The Plcγ2-P522R knock-in mouse model recapitulates the functional effects of the human PLCG2-P522R variant.
“we generated a Plcγ2-P522R knock-in (KI) mouse model using the CRISPR/Cas9 gene editing technology”
The paper relies on this without support.
Changes in total brain mRNA expression reflect changes in microglial gene expression.
“Although the origin of cell type-specific expression cannot be confirmed”
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?
Prior studies show mild effects of the PLCG2P522R variant on the microglial transcriptome in vitro or in healthy mice, but a stronger effect in the presence of pathology.
“This aligns with prior studies showing mild effects of the PLCG2P522R variant on the microglial transcriptome in vitro or in healthy mice, 27 , 29 but a stronger effect in the presence of pathology. 19 , 26 , 31”
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 [29]
In Findings, the paper reports moderate changes in microglia-associated genes in six-month-old knock-in mice, supporting the cited point about mild effects in mice without AD pathology. But the expression analysis used whole-brain tissue, not an isolated microglial transcriptome. The stronger effect in the presence of pathology is attached to other citations in the citing sentence, and this paper says studies with AD-associated pathology are still needed. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPrior investigations align with increased levels of CXCL1, IL-6, and TNFα in PLCG2P522R.
“The increased levels of CXCL1, IL‐6, and TNFα align with prior investigations, 19 , 24 , 29”
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 [29]
The Findings section reports significantly higher IL-6 and TNFα release from Plcγ2-P522R knock-in mouse macrophages than from wild-type cells after LPS and IFNγ stimulation. It reports IL-1β as the third elevated cytokine, not CXCL1; the Methods section likewise lists IL-1β rather than CXCL1 among the cytokines measured. This source therefore supports the IL-6 and TNFα parts of the claim, but not the CXCL1 part. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe TREM2-PLCγ2 signaling axis has been proposed to regulate phagocytosis, secretion of cytokines and chemokines, cell survival and proliferation in microglia.
“The TREM2-PLCγ2 signaling axis has been proposed to regulate phagocytosis, secretion of cytokines and chemokines, cell survival and proliferation in microglia [17, 36, 37].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [17]
The Findings (page not provided) identify PLCγ2 as part of TREM2 signaling in microglia and link that pathway to phagocytosis and cell survival. They also discuss proliferation through downstream signaling, but describe cytokine secretion in macrophages as occurring apart from TREM2-dependent signaling; they do not establish chemokine secretion through the TREM2–PLCγ2 axis. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe P522R-associated calcium changes are associated with improved survival, enhanced phagocytic/endocytic activity, and increased acute inflammatory response.
“Collectively, these changes are associated with improved survival, enhanced phagocytic/endocytic activity, and increased acute inflammatory response. 11 , 12”
From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [11]
The Findings section reports improved survival in P522R knock-in macrophages after growth-factor withdrawal, a stronger acute cytokine response to stimulation, and enhanced phagocytic activity in BV2 cells expressing P522R. The increase in phagocytosis in knock-in macrophages was not statistically significant. The paper measures increased Ip1 signaling, but does not establish that calcium changes produced these outcomes or separately demonstrate enhanced endocytic activity (Findings; no page given). (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn vitro studies have demonstrated that the P522R variant induces a slight increase in cytosolic calcium, both basally and upon stimulation, indicating mild hypermorphic activity.
“In vitro studies have demonstrated that the P522R variant induces a slight increase in cytosolic calcium, both basally and upon stimulation, indicating mild hypermorphic activity. 10 , 11 , 12”
From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [11]
The Findings section reports higher basal Ip1 levels in cultured P522R knock-in macrophages and interprets this as a mild hypermorphic effect on Plcγ2 enzyme activity. It does not report a measurement of cytosolic calcium, either basally or upon stimulation; the reported stimulated response concerns cytokine secretion. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The P522R mutation increases the release of inflammatory cytokines by microglia.
“Studies have shown that the P522R mutation increases the release of inflammatory cytokines by microglia, and has variable effects on phagocytosis depending on cargo size [13].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [13]
The Findings section reports increased TNFα, IL-6, and IL-1β release from P522R knock-in bone marrow-derived macrophages after LPS and IFNγ stimulation, not from microglia. It reports increased phagocytosis in BV2 microglia-like cells, but does not establish that the effect varies with cargo size. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe P522R mutation has variable effects on phagocytosis by microglia depending on cargo size.
“Studies have shown that the P522R mutation increases the release of inflammatory cytokines by microglia, and has variable effects on phagocytosis depending on cargo size [13].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [13]
The Findings section reports increased phagocytic activity in P522R-expressing BV2 microglia-like cells, but does not report that the effect varies with cargo size. It also reports increased inflammatory cytokine release from stimulated bone marrow-derived macrophages, not microglia. The Methods describe the phagocytosis cargo used in each assay without comparing cargo sizes; page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrevious studies showed that the P522R mutation was capable of increasing cytokine secretion in microglia.
“as previous studies showed that the P522R mutation was capable of increasing cytokine secretion in microglia [13].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [13]
The Findings section reports increased TNFα, IL-6, and IL-1β release from P522R knock-in bone marrow-derived macrophages after LPS and IFNγ stimulation. It separately reports signs of microglial activation, but does not show increased cytokine secretion by microglia. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhagocytic activity of iPSC-derived microglia-like cells has recently been shown to be reduced by PLCγ2 deficiency, whilst phagocytosis was enhanced in BMDMs expressing P522R.
“Phagocytic activity of iPSC-derived microglia-like cells has recently been shown to be reduced by PLCγ2 deficiency26, whilst phagocytosis was enhanced in bone marrow-derived macrophages that express the hypermorphic P522R variant19.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [19]
The Findings section reports approximately 45% higher phagocytic activity in P522R knock-in bone marrow-derived macrophages than in wild-type cells, but says the difference was not statistically significant (Fig. 1e). The cited paper therefore supports the direction of the observation, not an unqualified claim that phagocytosis was enhanced in those cells. The iPSC-derived microglia claim has a separate citation and is not judged here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPLCγ2 has been implicated in driving inflammatory responses in mouse BMDMs and iPSC microglia-like cells, via TLR and inflammasome activation.
“In addition to mediating TREM2-dependent signalling, PLCγ2 has been implicated in driving inflammatory responses in mouse BMDMs and in iPSC microglia-like cells, via TLR and inflammasome activation19,26.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [19]
In the Findings section (page not supplied), the paper reports enhanced cytokine release from stimulated mouse BMDMs and cites earlier work linking PLCγ2 depletion to impaired inflammatory responses in iPSC-derived microglia. It also says PLCγ2 mediates inflammatory responses through Toll-like receptors. The paper does not establish inflammasome activation as the mechanism for those cellular responses. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe PLCγ2-P522R variant increases the survival of mouse bone marrow-derived macrophages upon LPS treatment.
“We previously showed that the PLCγ2-P522R variant increases microglial activation in adult C57BL/6J mice and enhances the acute inflammatory response and increases the survival of mouse bone marrow-derived macrophages upon treatment with lipopolysaccharide (LPS) [7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
The Findings report enhanced survival of P522R knock-in bone marrow-derived macrophages after m-CSF withdrawal, not after LPS treatment. In a separate Findings passage, LPS plus IFNγ treatment produced a stronger inflammatory response; it was not reported as a survival test. Page numbers are not available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe protective PLCγ2-P522R variant increases microglia activation in WT mice with no β-amyloid pathology.
“We have previously shown that the protective PLCγ2-P522R (rs72824905, p.P522R, Fig. 1A) variant increases microglia activation in WT mice with no β-amyloid pathology [7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
The Findings section reports that RNA pathway analysis suggested higher microglial activation in Plcγ2-P522R knock-in mice than in WT littermates. It also says studies with AD-associated pathology are still needed, consistent with the absence of that pathology here. The claim is imprecise in saying the increase occurred in WT mice: the variant-bearing mice were knock-ins, and WT mice were the comparator. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe PLCγ2-P522R variant enhances the acute inflammatory response in mouse bone marrow-derived macrophages upon LPS treatment.
“We previously showed that the PLCγ2-P522R variant increases microglial activation in adult C57BL/6J mice and enhances the acute inflammatory response and increases the survival of mouse bone marrow-derived macrophages upon treatment with lipopolysaccharide (LPS) [7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
The Findings report that bone marrow-derived macrophages from P522R knock-in mice released significantly more inflammatory cytokines than wild-type cells after stimulation. The treatment was LPS together with interferon-gamma (IFNγ), not LPS alone, so the stated treatment condition is incomplete. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn 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].”
From PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease (2022) · cites this paper as [13]
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 measuredMissense hypermorphic variants of PLCG2 confer a reduced risk for Alzheimer's disease.
“While missense hypermorphic variants of PLCG2 confer a reduced risk for AD, the mechanistic role that PLCγ2 plays in AD pathogenesis is unclear [44–48].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [46]
The Findings identify one PLCG2 variant, P522R, as associated with reduced Alzheimer’s disease risk. The section on enzyme activity describes P522R as mildly hypermorphic, but does not establish that hypermorphic PLCG2 variants generally reduce that risk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCells derived from P522R knock-in mice had an increased capacity to phagocytose pHrodo-labelled zymosan compared to WT BMDMs.
“Studies in mouse BMDMs revealed that cells derived from P522R KI mice had an increased capacity to phagocytose pHrodo-labelled zymosan, in comparison to WT BMDMs [35]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
The Methods (BMDM phagocytosis assay) confirm that KI and WT BMDMs were tested with pHrodo-labelled zymosan. The Findings report about 45% higher phagocytic activity in KI BMDMs, but explicitly say the difference was not statistically significant; the claim omits that qualification. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe PLCγ2 p.P522R variant causes an increase in microglial phagocytosis and survival, whereas TREM2 LOAD variants typically induce a reduction in these phenotypes.
“Whilst TREM2 LOAD variants typically induce a reduction in microglial phagocytosis and survival, the PLCγ2 p.P522R variant causes an increase in these beneficial microglial phenotypes [35, 36]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
The Findings report increased phagocytosis in P522R-expressing microglia-like BV2 cells and enhanced survival in P522R knock-in bone marrow-derived macrophages, not directly in microglia. They also describe impaired microglial survival with TREM2 deficiency and propose opposite effects for TREM2 risk and PLCγ2 protective variants, but do not establish that TREM2 LOAD variants typically reduce both phenotypes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPET imaging using the 18F-FPEA probe to detect TSPO activity revealed that P522R knock-in mice showed an increase in microglial activity compared to WT littermates.
“Positron Emission Tomography imaging, using the 18F-FPEA probe to detect Translocator Protein (TSPO) activity, revealed that P522R Knock-In (KI) mice showed an increase in microglial activity when compared to WT littermates [35]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
The Findings section reports significantly higher TSPO PET signal in one-year-old Plcγ2-P522R knock-in female mice than in WT females and interprets it as increased microglial activation. However, the radioligand was 18F-FEPPA, not the claim’s 18F-FPEA. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPLCγ2 activation in microglia, monocyte/macrophages, dendritic and mast cells has been linked to increased cytokine production.
“PLCγ2 activation in microglia, monocyte/macrophages, dendritic and mast cells has been linked to increased cytokine production [32, 35]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
The Findings section (page not provided) reports that macrophages carrying the PLCγ2-P522R variant released more TNFα, IL-6 and IL-1β after LPS and IFNγ stimulation. The paper also links PLCγ2 signaling to cytokine production generally, but does not establish increased cytokine production across all the listed cell types, particularly mast cells; its microglial findings concern other functions. The claim therefore extends beyond what this source shows. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPLCG2 P522R mice exhibit an altered microglial gene expression profile involving genes linked to PLC signaling and pathways related to survival, proliferation, and inflammatory responses.
“PLCG2 P522R mice also exhibit an altered microglial gene expression profile involving genes linked to PLC signaling and pathways related to survival, proliferation, and inflammatory responses 16 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [16]
The Findings section (‘The mRNA profile associated with Plcγ2-P522R’) reports altered expression of genes linked to Plcγ2 signaling in knock-in mice and connects Mapk/Erk signaling to survival, proliferation, and inflammatory responses. However, expression was measured in total brain tissue, not isolated microglia; the authors infer altered microglial activation from those data rather than directly establishing a microglial gene expression profile. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPLCG2 regulates the expression of genes governing pathways related to inflammation, lipid metabolism, microglial viability and phagocytosis.
“PLCG2 regulates the expression of genes governing pathways related to inflammation, lipid metabolism, microglial viability and phagocytosis 12,16 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [16]
In the Findings section on the mRNA profile, the paper reports altered expression of genes linked to inflammatory responses, survival and phagocytosis in Plcγ2-P522R knock-in mouse brains. It also reports increased Apoe expression, but says only that the variant moderately increases a subset of disease-associated microglial genes, which include lipid-metabolism-associated genes. The categorical claim that PLCG2 regulates gene expression across all four pathways is stronger than these variant-specific, qualified findings. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe P522R variant enhances cellular survival.
“This finding supports previous studies showing that the P522R variant enhances cellular survival 29 .”
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 [29]
The PLCγ2 P522R protective variant is a functional hypermorph.
“The phospholipase C-γ−2 (PLCγ2) P522R protective variant is a functional hypermorph (12–16), while it is predicted that M28L is a loss-of-function variant (17).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [14]
In vivo studies of the P522R variant have been limited to wild-type (non-AD) P522R knock-in mice, which reported a trend toward increased expression of Cst7, Tyrobp, Clec7a, and Ccl3 by quantitative polymerase chain reaction of total brain mRNA.
“Despite this recent progress, studies of the P522R variant in vivo have thus far remained limited to the examination of wild‐type (non‐AD) P522R knock‐in (KI) mice, which reported a trend toward increased expression of Cst7, Tyrobp, Clec7a, and Ccl3 by quantitative polymerase chain reaction of total brain mRNA. 11 , 12”
From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [11]
PLCG2 was believed to be almost exclusively expressed in microglia and has been extensively investigated in this cell type.
“this AD risk gene was believed to be almost exclusively expressed in microglia and, as a consequence, it has been extensively investigated in this cell type18–21.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [18]
In AD, PLCG2 has been mostly studied in microglia and shown to be implicated in multiple microglia-related signaling pathways.
“In AD, PLCG2 has been mostly studied in microglia and shown to be implicated in multiple microglia-related signaling pathways18–21.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [18]
In the brains of Plcγ2-P522R knock-in mice, Akt1/2 phosphorylation was reduced, casting doubt on the AKT hypothesis.
“in the brains of Plcγ2-P522R knock-in mice, Akt1/2 phosphorylation was reduced, casting doubt on this hypothesis18.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [18]
In microglia, PLCγ2 functions as a key downstream effector for TREM2 and TLRs.
“In microglia, PLCγ2 functions as a key downstream effector for triggering receptor expressed on myeloid cells 2 (TREM2) and Toll-like receptors (TLRs) [6, 7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
The PLCγ2-P522R variant increases microglial activation in adult C57BL/6J mice.
“We previously showed that the PLCγ2-P522R variant increases microglial activation in adult C57BL/6J mice and enhances the acute inflammatory response and increases the survival of mouse bone marrow-derived macrophages upon treatment with lipopolysaccharide (LPS) [7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
The PLCγ2-P522R variant is a functional hypermorph that mildly increases PLCγ2 enzyme activity.
“PLCγ2-P522R is a functional hypermorph that mildly increases PLCγ2 enzyme activity [3, 6, 7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
PLCγ2-P522R KI mouse macrophages respond more efficiently to LPS- and IFNγ-induced inflammation than wild-type cells do.
“We previously showed that PLCγ2-P522R KI mouse macrophages respond more efficiently to LPS- and IFNγ-induced inflammation than wild-type cells do [7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
AKT activation is decreased in the PLCγ2-P522R mouse brain, possibly due to increased consumption of PIP2 by PLCγ2 and consequently reduced PIP3 resources for promoting PI3K-AKT signaling.
“we have previously shown that AKT activation is decreased in the PLCγ2-P522R mouse brain, possibly due to increased consumption of PIP2 by PLCγ2 and consequently reduced PIP3 resources for promoting PI3K-AKT signaling [7].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [7]
PLCG2-P522R potentiates PLCγ2 function and mediates several beneficial effects on microglia function in in vivo and in vitro models.
“PLCG2-P522R, which potentiates PLCγ2 function, mediates several beneficial effects on microglia function in in vivo and in vitro models [5–10].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [8]
The P522R variant is a mild hypermorph that potentiates the enzymatic activity of PLCγ2.
“Recent studies have suggested that the P522R variant is a mild hypermorph [15–17], serving to potentiate the enzymatic activity of the protein”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [17]
A previous study has suggested that the P522R variant may promote microglial activation, indicating a role for PLCγ2 in microglial activation state.
“A previous study has suggested that the P522R variant may promote microglial activation [17], hence indicating a role for this protein in microglial activation state.”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [17]
The P522R variant enhances macrophage phagocytic activity and cytokine release in response to inflammatory stimulation, and may promote microglial activation.
“It has been shown that this altered activity appears to enhance macrophage phagocytic activity and enhance cytokine release in response to inflammatory stimulation, and may promote microglial activation [17]”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [17]
These heterozygous cells may be 'primed' to more readily respond to an inflammatory challenge, and can therefore more efficiently uptake and phagocytose targets such as Aβ when required.
“This may suggest that these heterozygous cells are ‘primed’ to more readily respond to an inflammatory challenge, and can, therefore, more efficiently uptake and phagocytose targets such as Aβ when required, a hypothesis supported by recent work suggesting that PLCγ2P522R may promote microglial activation [17].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [17]
A broad spectrum of gene expression changes have also been reported in homozygous PLCγ2P522R knock-in mice.
“A broad spectrum of gene expression changes have also been reported in homozygous PLCγ2P522R knock-in mice [17].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [17]
In a small cohort of Plcg2 R522 knock-in mice, enhanced microglial activity was reported.
“An initial study in a small cohort of Plcg2 R522 knock‐in mice reported enhanced microglial activity (Takalo et al. 2020).”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Takalo et al. 2020
It has been previously reported that Plcg2 R522 expression may enhance the inflammatory response to a limited in vitro challenge.
“It has been previously reported that Plcg2 R522 expression may enhance the inflammatory response to a limited in vitro challenge (Takalo et al. 2020), hence we elected to conduct a time course analysis of cytokine responses to the model microbial challenge, LPS, or Aβ1‐42.”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Takalo et al. 2020
Enhanced microglial activity in Plcg2 R522 expressing adult wildtype mice has been previously described.
“This aligns with a prior description of enhanced microglial activity in Plcg2 R522 expressing adult wildtype mice (Takalo et al. 2020).”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Takalo et al. 2020
Several studies have suggested that the protective role of the P522R PLCγ2 variant is linked to functional effects on microglia.
“Several studies have suggested that the protective role of the P522R PLCγ2 variant is linked to functional effects on microglia (Maguire et al., 2021;Takalo et al., 2020;Tsai et al., 2023).”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Takalo et al., 2020
Several studies directly focusing on the PLCγ2 P522R variant support its role in different aspects of phagocytosis as a cellular mechanism towards AD protection.
“Several studies directly focusing on the PLCγ2 P522R variant support its role in different aspects of phagocytosis as a cellular mechanism towards AD protection (Solomon et al., 2022;Takalo et al., 2020;Tsai et al., 2023).”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Takalo et al., 2020
Enhanced IP1 production has been observed in growing bone marrow-derived macrophages from PLCγ2 P522R knock-in mice.
“With respect to PLC activity, some of these studies have demonstrated that microglia and macrophages from PLCγ2 P522R knock-in (KI) mice have enhanced calcium responses following stimulation (Maguire et al., 2021); similarly, an enhanced IP1 production has been observed in growing bone marrow-derived macrophages (BMDMs) from the KI mice (Takalo et al., 2020).”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Takalo et al., 2020
PLCγ2 p.P522R is associated with improved survival and increased inflammatory responses.
“Improved survival, increased inflammatory responses [35]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
p.P522R increases BMDM survival after withdrawal of macrophage colony-stimulating factor.
“Importantly, the p.P522R variant increases BMDM survival after withdrawal of the macrophage colony-stimulating factor [35]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
BMDMs from mice harbouring p.P522R have increased basal IP1 levels compared to WT.
“BMDMs from mice harbouring the p.P522R variant, were found to have increased basal IP1 levels when compared to WT [35]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [35]
PLCG2 P522R is a mild hypermorph.
“A genetic variant of PLCG2, PLCG2 P522R , is a mild hypermorph that attenuates AD risk.”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [16]
Knockin PLCG2 P522R mice show modestly increased basal phospholipase activity.
“Knockin PLCG2 P522R mice show modestly increased basal phospholipase activity 16 and macrophages with improved survival and viability, increased basal phagocytic activity, and, unexpectedly, elevated cytokine secretion 16 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [16]
PLCG2 P522R shows slightly elevated activity.
“PLCG2 P522R shows slightly elevated activity 11,16,34”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [16]
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.
Cytochalasin D concentration differs between caption and methods
MinorThe Figure 1e caption identifies the phagocytosis control as 5 μM Cytochalasin D, while the BMDM phagocytosis method specifies 10 μM.
“Cytochalasin D (CytD, 5 μM) was used as a control.”
“Phagocytosis was initiated by adding 5 μg/well pHrodo-labeled bioparticles (pHrodo™ Red Zymosan BioParticles™ Conjugate for Phagocytosis, ThermoFisher Scientific, P35364) with or without 10 μM Cytochalasin D.”
Figure 2 immunoblot is cited as panel c instead of d
MinorThe text cites Fig. 2c for the Erk and Akt phosphorylation results, but the figure caption assigns the immunoblot and its quantitation to panel d. Panel c contains immunostaining images and measurements.
“Activity-related phosphorylation of Mapk1/Erk2 (Y204) remained unaltered in the brain of KI mice, whereas the Mapk3/Erk1 phospho-protein was undetectable (Fig. 2c). However, activity-related phosphorylation of Akt1/2 (S473/474) was significantly reduced in the brain of KI mice (Fig. 2c).”
“D) Immunoblot showing phosphorylation status and total levels of Mapk/Erk and Akt in the total brain lysates of the WT and KI mice.”
FDG analysis window extends beyond the stated scan duration
MinorThe Figure 3b caption specifies an 18F-FDG uptake window ending at 80 minutes, but the PET method states that dynamic imaging lasted 70 minutes.
“b Representative PET images of the uptake of 18F-FDG (time window 20-80 min) in WT and KI mouse (upper panel).”
“Dynamic imaging of 70 min was started at the time of the administration of the activity (18F-FEPPA: 15.8 ± 1.4 MBq and 18F-FDG: 13.9 ± 1.2 MBq) through the tail vein.”
Microglia measurements are cited as a nonexistent Figure 2e
MinorThe text assigns the microglia number, morphology, and P2ry12 measurements to Fig. 2e, whereas the caption places those measurements in panel c and describes panels only through d.
“Immunohistochemical analysis of the microglia marker Iba1 did not show significant alterations in microglia number or morphology in the brain of KI mice as compared to WT mice (Fig. 2e). The levels of a microglia-specific purinergic receptor P2ry12 were significantly higher in the cortex of KI mice as compared to WT mice (Fig. 2e)”
“c Representative images (left) of Iba1, P2ry12, and Gfap-stained cortex or hippocampus from WT and KI mice. Quantitation (right) of Iba1-positive microglia, microglia morphology, P2ry12, and Gfap levels.”
LDH technical-replicate counts disagree
MinorThe Figure 1d caption reports two technical replicates, but the LDH assay method says medium was collected from triplicate wells per sample.
“Mean ± SD, % of WT (4 h), n = 3–4 per genotype, 2 technical replicates.”
“Medium samples from triplicate wells per sample were collected 4 h, 24 h and 48 h after m-CSF withdrawal.”
BV2 fluorescence intensity has conflicting normalization groups
MinorThe Figure 1f caption presents the phagocytosis measurements as a percentage of the control-vector group, but the BV2 assay method says MFI was normalized to the PLCγ2-WT group.
“Mean ± SD, % of CTRL, n = 4.”
“MFI was normalized to the WT group.”
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BackgroundMethodInfluentialTREM-2 promotes macrophage survival and lung disease after respiratory viral infection
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Tauopathies: new perspectives and challenges
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Self-citationEmerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
Lewcock, J. W., Schlepckow, K., Di Paolo, G., Tahirovic, S., Monroe, K. M., & Haass, C. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.029 · Cited by 221 · see citing works
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“Recently, a PLCγ2 mutation (P522R) that results in a functional hypermorph that enhances the PIP2-metabolizing function of PLCγ2 has been identified as a protective mutation against AD [53, 65, 80].”
BackgroundTREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
Li, Y., Xu, H., Wang, H., Yang, K., Luan, J., & Wang, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115218 · Cited by 128 · see citing works
Microglial efferocytosis: Diving into the Alzheimer’s disease gene pool
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Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
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Moving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer’s disease
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Alzheimer’s disease – the journey of a healthy brain into organ failure
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Application of CRISPR/Cas9 in Alzheimer’s Disease
Lu, L., Xi, Y., Cai, Y., Sun, M., & Yang, H. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.803894 · Cited by 78 · see citing works
Tsai, A. P., Dong, C., Lin, P. B.-C., Oblak, A. L., Viana Di Prisco, G., Wang, N., Hajicek, N., Carr, A. J., Lendy, E. K., Hahn, O., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.08.008 · Cited by 71 · see citing works
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“P522R variant causes an increase in these beneficial microglial phenotypes [35, 36].”
BackgroundResultInfluentialXu, Y., Au, N. P. B., & Ma, C. H. E. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.896852 · Cited by 67 · see citing works
“At the early stage of AD, activated microglia were able to clear Aβ by phagocytosis (Takata et al., 2010).”
BackgroundClaes, C., England, W. E., Danhash, E. P., Kiani Shabestari, S., Jairaman, A., Chadarevian, J. P., Hasselmann, J., Tsai, A. P., Coburn, M. A., Sanchez, J., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12577 · Cited by 52 · see citing works
Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders
Plano, L. M. D., Calabrese, G., Sabrina Conoci, A., Guglielmino, S. P. P., Oddo, S., & Caccamo, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158714 · Cited by 54 · see citing works
“Among these, the Plcγ2-P522R variant reduces the risk of developing AD [53].”
BackgroundThe aging immune system in Alzheimer’s and Parkinson’s diseases
Heavener, K. S., & Bradshaw, E. M. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00944-6 · Cited by 50 · see citing works
“For example, the AD-protective allele in the PLCG2 gene leads to a proline to arginine amino acid change, and this mutation results in enhanced immune signaling [96, 97].”
BackgroundGao, C., Shen, X., Tan, Y., & Chen, S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02580-1 · Cited by 43 · see citing works
Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease
Khani, M., Gibbons, E., Bras, J., & Guerreiro, R. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00505-9 · Cited by 39 · see citing works
“The variant is located in a regulatory domain, conferring a small hypermorphic effect on enzyme activity [75] and has been shown to enhance microglial functions in a Plcγ2P522R knock-in mouse model [76].”
BackgroundMicroglial TREM2 at the Intersection of Brain Aging and Alzheimer’s Disease
Qu, W., & Li, L. (2021) · The Neuroscientist · doi:10.1177/10738584211040786 · Cited by 37 · see citing works
Obst, J., Hall-Roberts, H. L., Smith, T. B., Kreuzer, M., Magno, L., Di Daniel, E., Davis, J. B., & Mead, E. (2021) · Scientific Reports · doi:10.1038/s41598-021-96144-7 · Cited by 36 · see citing works
Lipid Homeostasis and Its Links With Protein Misfolding Diseases
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“A related role has been described for PLCG2, which encodes phospholipase Cγ2, a lipid-processing enzyme that cleaves phosphatidylinositol-4,5-bisphosphate to diacylglycerol and inositol-1,4,5-trisphosphate (Andreone et al., 2020; Takalo et al., 2020).”
BackgroundArtificial intelligence for dementia genetics and omics
Bettencourt, C., Skene, N., Bandres‐Ciga, S., Anderson, E., Winchester, L. M., Foote, I. F., Schwartzentruber, J., Botia, J. A., Nalls, M., Singleton, A., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13427 · Cited by 30 · see citing works
Targeting PKC in microglia to promote remyelination and repair in the CNS
Kim, P. M., & Kornberg, M. D. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.11.008 · Cited by 24 · see citing works
CRISPR-Cas9 in Alzheimer’s disease: Therapeutic trends, modalities, and challenges
Chacko, L., Chaudhary, A., Singh, B., Dewanjee, S., & Kandimalla, R. J. L. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103652 · Cited by 25 · see citing works
Solomon, S., Sampathkumar, N. K., Carre, I., Mondal, M., Chennell, G., Vernon, A. C., Ruepp, M.-D., & Mitchell, J. C. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04473-1 · Cited by 23 · see citing works
“This may suggest that these heterozygous cells are ‘primed’ to more readily respond to an inflammatory challenge, and can, therefore, more efficiently uptake and phagocytose targets such as Aβ when required, a hypothesis supported by recent work suggesting that PLCγ2P522R may promote microglial activation [17].”
BackgroundInfluentialImmune dysfunction in Alzheimer disease
Butovsky, O., Rosenzweig, N., Kleemann, K. L., Jorfi, M., Kuchroo, V. K., Tanzi, R. E., & Weiner, H. L. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00997-0 · Cited by 34 · see citing works
“Review article response 181 .”
Zhao, Y., Guo, Q., Tian, J., Liu, W., & Wang, X. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102596 · Cited by 22 · see citing works
Alzheimer’s Disease Genetics: A Dampened Microglial Response?
Chatila, Z. K., & Bradshaw, E. M. (2021) · The Neuroscientist · doi:10.1177/10738584211024531 · Cited by 20 · see citing works
Yashooa, R. K., Nabi, A. Q., Smail, S. W., Azeez, S. S., Nooh, W. A., Mustafa, S. A., Al-Farha, A. A.-B., Capitanio, N., & Shekha, M. S. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2025.1737468 · Cited by 20 · see citing works
“CRISPRa employ dCas9 fused to transcriptional activators to upregulate gene expression, while CRISPRi use dCas9-repressor fusions to silence gene transcription, facilitating functional genomics studies and potential therapeutic gene modulation (68, 69).”
Li, K., Ran, B., Wang, Y., Liu, L., & Li, W. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.999061 · Cited by 18 · see citing works
PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology
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., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70231 · Cited by 16 · see citing works
Rahimi, A., Sameei, P., Mousavi, S., Ghaderi, K., Hassani, A., Hassani, S., & Alipour, S. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04143-2 · Cited by 17 · see citing works
“2) [143].”
Takalo, M., Jeskanen, H., Rolova, T., Kervinen, I., Hellén, M., Heikkinen, S., Koivisto, H., Jokivarsi, K., Müller, S. A., Koivumäki, E.-M., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03387-6 · Cited by 15 · see citing works
“In this study, the APPswe/PS1dE9 transgenic mouse line (later simply APP/PS1) [19] was crossbred with the PLCγ2-P522R knock-in (KI) mouse line [7] to investigate the effects of the PLCγ2-P522R variant on AD-related β-amyloid and associated neuronal pathologies, microglial activation, and behavioral…”
InfluentialSelf-citationVilla-Roel, N., Park, C., Andueza, A., Baek, K., Su, A. J., Blaser, M., Leshnower, B. G., Yoganathan, A., Aikawa, E., & Jo, H. (2024) · Genes · doi:10.3390/genes15121623 · Cited by 15 · see citing works
Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system
Diks, A. M., Teodosio, C., de Mooij, B., Groenland, R. J., Naber, B. A. E., de Laat, I. F., Vloemans, S. A., Rohde, S., de Jonge, M. I., Lorenz, L., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00604-9 · Cited by 14 · see citing works
“P522R microglia-like cells (BV2 cell-line) and homozygous knock-in murine macrophages, as determined by pHRodoTM Green signal and percentage of phagocytosing cells [14].”
BackgroundMethodHe, S., Qiu, S., Pan, M., Palavicini, J. P., Wang, H., Li, X., Bhattacharjee, A., Barannikov, S., Bieniek, K. F., Dupree, J. L., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1332 · Cited by 11 · see citing works
Functional insight into LOAD-associated microglial response genes
Jonas, L. A., Jain, T., & Li, Y. (2022) · Open Biology · doi:10.1098/rsob.210280 · Cited by 13 · see citing works
Therapeutic targeting of neuroimmune mechanisms in neurodegeneration
Monroe, K. M., Hong, S. Y., Lewcock, J. W., & Yang, A. C. (2026) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01370-7 · Cited by 14 · see citing works
A landscape of the genetic and cellular heterogeneity in Alzheimer diseasePreprint
Brase, L., You, S., Albanus, R. D., Del‐Aguila, J. L., Dai, Y., Novotny, B. C., Soriano‐Tárraga, C., Dykstra, T., Fernández, M. V., Budde, J., et al. (2021) · medRxiv · doi:10.1101/2021.11.30.21267072 · Cited by 10 · see citing works
Staley, H. A., Jernigan, J. E., Bolen, M. L., Titus, A. M., Neighbarger, N., Cole, C., Menees, K. B., Wallings, R. L., & Tansey, M. G. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03271-9 · Cited by 9 · see citing works
“Further functional assays surveyed inflammatory cytokine secretion by pMacs from females and males, as previous studies showed that the P522R mutation was capable of increasing cytokine secretion in microglia [13].”
BackgroundMethodPLCG2 rs72824905 Variant Reduces the Risk of Alzheimer’s Disease and Multiple Sclerosis
Chen, F., Zhang, Y., Wang, L., Wang, T., Han, Z., Zhang, H., Gao, S., Hu, Y., & Liu, G. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201140 · Cited by 9 · see citing works
Bedford, L. M., Tutrow, K. D., Hooper, K., Messenger, E. J., Hernandez, M., Lamb, B. T., Meyer, J. S., Richardson, T. I., & Bissel, S. J. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70772 · Cited by 8 · see citing works
“This aligns with prior studies showing mild effects of the PLCG2 P522R variant on the microglial transcriptome in vitro or in healthy mice, 27,29 but a stronger effect in the presence of pathology.”
Role and application of CRISPR-Cas9 in the management of Alzheimer’s disease
Soni, N., Kar, I., Narendrasinh, J. D., Shah, S. K., Konathala, L., Mohamed, N., Kachhadia, M. P., Chaudhary, M. H., Dave, V. A., Kumar, L., et al. (2024) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000001692 · Cited by 9 · see citing works
“Various groups have developed nanocomplexes of non-viral delivery vehicles and Cas9 activator with outstanding probable therapeutic uses, including for neural illnesses, to aid in the administration of Cas9 activators [30,31] .”
BackgroundCharacterisation of molecular mechanisms for PLCγ2 disease-linked variants
Bunney, T. D., Kampyli, C., Gregory, A., & Katan, M. (2024) · Advances in Biological Regulation · doi:10.1016/j.jbior.2024.101053 · Cited by 8 · see citing works
Pandya, K., & Kumar, D. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102922 · Cited by 9 · see citing works
Akintade, D. D., & Chaudhuri, B. (2020) · Bioscience Reports · doi:10.1042/bsr20201912 · Cited by 8 · see citing works
RetractedNetwork Dynamics‐based Subtyping of Alzheimer's Disease With Microglial Genetic Risk Factors
Choi, J. H., Lee, J., Kang, U., Chang, H., & Cho, K.-H. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01583-9 · Cited by 7 · see citing works
Zhang, X., Wang, R., Pan, X., Chen, Z., Li, Y., Hu, Y., Liu, F., & Cao, X. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04820-w · Cited by 8 · see citing works
“In microglia, PLCγ2 influences essential functions such as cell survival, debris clearance, and lipid metabolism downstream of TREM2 [25, 44].”
Shin, Y.-C., Plummer-Medeiros, A. M., Mungenast, A., Choi, H.-W., TenDyke, K., Zhu, X., Shepard, J., Sanders, K., Zhuang, N., Hu, L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adn6037 · Cited by 7 · see citing works
Swain, P. S., Panda, S., Pati, S., & Dehury, B. (2023) · Journal of Molecular Modeling · doi:10.1007/s00894-023-05770-7 · Cited by 6 · see citing works
“As a result, TREM2’s ability to guard against AD will be diminished [18].”
BackgroundLi, J., Liu, L., Sun, S., Liu, C., & Yin, P. (2026) · Medicine · doi:10.1097/md.0000000000046851 · Cited by 5 · see citing works
“[97] Huangpu Tongqiao capsules can ameliorate learning and memory deficits in AD rat models, potentially via modulation of the EGFR-PLC γ signaling axis.”
Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain
Hopp, S. C., Rogers, J. G., Smith, S., Campos, G., Miller, H., Barannikov, S., Kuri, E. G., Wang, H., Han, X., Bieniek, K. F., et al. (2023) · doi:10.1101/2023.12.06.570499 · Cited by 4 · see citing works
“The TREM2/PLCγ2 signaling axis has been proposed to regulate phagocytosis, secretion of cytokines and chemokines, cell survival and proliferation (14, 24, 25).”
BackgroundPhosphoinositide-specific phospholipase C enzymes: Recent advances in a long journey
Macrae, C., Lalović, D., Bunney, T. D., & Katan, M. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2025.159627 · Cited by 4 · see citing works
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Carr, A. J., Hajicek, N., Tsai, A. P., Acharya, P. P., Hardy, P. B., Meyer, E. G., Wyss‐Coray, T., Pearce, K. H., Sondek, J., & Zhang, Q. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108356 · Cited by 5 · see citing works
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Visvanathan, R., Utsuki, T., Beck, D. E., Lendy, E. K., Sun, K.-L., Liu, Y., Hering, K. W., Mesecar, A. D., Zhang, Z., & Putt, K. S. (2023) · SLAS DISCOVERY · doi:10.1016/j.slasd.2023.03.003 · Cited by 3 · see citing works
Genetic modification of mice using CRISPR-Cas9: Best practices and practical concepts explained
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Dehestani, M., Kessler, W., Karmali, N., Sun, W., Volos, P., Tsitkov, S., Dhingra, A., Rodrı́guez-Nieto, S., Tietz, J., Schafflick, D., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.01.601392 · Cited by 3 · see citing works
“The up-regulation of LRRK2 in PD OPCs and proliferating OPCs, along with RIT2 (a PD risk gene[48]) and PLCG2 (a phagocytosis-and immune-related gene[49]), consequently resulted in the enrichment of calcium-mediated signaling GO term.”
BackgroundGlia in Neurodegenerative DiseasePreprint
Crowley, G., Attwell, D., Phatnani, H. P., Sontheimer, H. W., & Hong, S. Y. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041375 · Cited by 3 · see citing works
“…PLCG2, where a mild gain-of-function genetic variant (P522R) is associated with lowering the risk of AD, dementia with Lewy bodies, and FTD (Sims et al. 2017), has been shown to act downstream from TREM2 to boost microglial metabolism and lipid processing (Andreone et al. 2020; Takalo et al. 2020).”
Using Genome Editing for Alzheimer’s Disease Therapy: from Experiment to Clinic
Stepanichev, M. Y. (2021) · Neurochemical Journal · doi:10.1134/s1819712421040139 · Cited by 2 · see citing works
Nerve Growth Factor Compromise in Down Syndrome
Carmo, S. D., Kannel, B., & Cuello, A. C. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.719507 · Cited by 2 · see citing works
Plaque attack by microglial PLCγ2
Comer, A. L., & Hammond, T. R. (2023) · Immunity · doi:10.1016/j.immuni.2023.08.012 · Cited by 2 · see citing works
Jeskanen, H., Heikkinen, S., Kervinen, I., Lehtisalo, J., Ngandu, T., Willman, R.-M., Rosa, J., Hoffmann, D., FinnGen, Leinonen, V., et al. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-01957-1 · Cited by 1 · see citing works
Self-citationCoulon, A., Rabiller, F., Takalo, M., Roy, A., Pelletier, A., Martiskainen, H., Siedlecki-Wullich, D., Lannette-Weimann, N., Majerníková, N., Grenon, A., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02709-5 · Cited by 1 · see citing works
“However, in the brains of Plcγ2-P522R knock-in mice, Akt1/2 phosphorylation was reduced, casting doubt on this hypothesis 18 .”
Self-citationGenetic Modulators of Disease Penetrance
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Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging
Mangalmurti, A., Bonheur, A., & Lukens, J. R. (2026) · Journal of Molecular Biology · doi:10.1016/j.jmb.2026.169910 · Cited by 1 · see citing works
Bevan, R. J., Maguire, E., Mackinnon, E., Salis, E., Phillips, T., Simonazzi, E., Vassileva, M., Allen, N. D., Williams, J., & Taylor, P. R. (2026) · Glia · doi:10.1002/glia.70192 · Cited by 1 · see citing works
“An initial study in a small cohort of Plcg2 R522 knock-in mice reported enhanced microglial activity (Takalo et al. 2020).”
InfluentialSolomon, S., Sampathkumar, N. K., Carre, I., Mondal, M., Chennell, G., Vernon, A. C., Ruepp, M., & Mitchell, J. C. (2022) · Research Square · doi:10.21203/rs.3.rs-1420006/v2 · Cited by 1 · see citing works
Reddy, J. S., Wang, X., Allen, M., Carrasquillo, M. M., Biernacka, J. M., Jenkins, G. D., Coombes, B. J., Belbin, O., Golde, T. E., Ertekin‐Taner, N., et al. (2022) · medRxiv · doi:10.1101/2022.07.12.22277557 · Cited by 2 · see citing works
“associated with variants in immune genes identified in this study is entirely consistent with risk associated with TREM2 and PLCG2 variants [61-64].”
ResultGutierrez-Kuri, E., Marie Garcia-Rogers, J. L., Perez, J., Smith, S., Kenwood, M. R., Archuleta, K. S., Xiao, Y., Campos, G., Barannikov, S., Wang, H., et al. (2026) · doi:10.64898/2026.07.13.738356
Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease
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Solomon, S., Sampathkumar, N. K., Carre, I., Mondal, M., Chennell, G., Vernon, A. C., Ruepp, M., & Mitchell, J. C. (2022) · Research Square · doi:10.21203/rs.3.rs-1420006/v1
Takalo, M., Jeskanen, H., Rõlova, T., Kervinen, I., Hellén, M., Heikkinen, S., Koivisto, H., Jokivarsi, K. T., Müller, S. A., Koivumäki, E.-M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.12.612207
Self-citationThe protective PLCG2 variants delay Alzheimer's disease onset age in APOE ϵ4 carriersPreprint
Jeskanen, H., Heikkinen, S., Kervinen, I., Lehtisalo, J., Ngandu, T., Willman, R.-M., Rosa, J., Hoffmann, D., FinnGen, Leinonen, V., et al. (2025) · medRxiv · doi:10.1101/2025.09.22.25336304
Self-citationGenetics of PLCG2 expression and splicing relative to Alzheimer’s disease risk
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PLCG2 signaling and genetic resilience in Alzheimer’s disease
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Phosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in gliaPreprint
Storer, F., MacKinnon, E. A., Clarke, H., Maddison, D. C., Amadio, L., Susobhanan, T., Malik, B. R., Peters, O. M., & Smith, G. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.04.729572
Karmali, N., Kessler, W., Dehestani, M., Sun, W., Drwesh, L., Volos, P., Tsitkov, S., Dhingra, A., Thomas, C., Rodrı́guez-Nieto, S., et al. (2026) · iScience · doi:10.1016/j.isci.2026.116368 · Cited by 3 · see citing works
“The upregulation of LRRK2 in PD OPCs and proliferating OPCs, along with RIT2 (a PD risk gene 48 ) and PLCG2 (a phagocytosis-and immune-related gene 49 ), consequently resulted in the enrichment of calcium-mediated signaling GO term.”
Maguire, E., Menzies, G. E., Phillips, T., Sasner, M., Williams, H. M., Czubala, M. A., Evans, N., Cope, E. L., Sims, R., Howell, G. R., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020105603 · Cited by 41 · see citing works
“Takalo et al (2020) recently showed that R522 variant macrophages treated with a high dose of LPS and IFN c release a slightly increased amount of proinflammatory cytokines after 3 h compared to P522-expressing macrophages.”
Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells
Jing, H., Reed, A., Ulanovskaya, O. A., Grigoleit, J.-S., Herbst, D. M., Henry, C. L., Li, H., Barbas, S., Germain, J., Masuda, K., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112971118 · Cited by 24 · see citing works
“For example, PLCγ2_P522R, which has been reported to weakly stimulate PLCγ2 catalytic activity (20) and promote beneficial microglial function (34), has been linked to protection against LOAD (10).”
BackgroundResult
- Authors
- Takalo, M., Wittrahm, R., Wefers, B., Parhizkar, S., Jokivarsi, K., Kuulasmaa, T., Mäkinen, P., Martiskainen, H., Wurst, W., Xiang, X., Marttinen, M., Poutiainen, P., Haapasalo, A., Hiltunen, M., & Haass, C.
- Affiliations
- University of Eastern Finland (FI)
- German Center for Neurodegenerative Diseases (DE)
- Ludwig-Maximilians-Universität München (DE)
- Kuopio University Hospital (FI)
- Corresponding author
- Hiltunen, Mikko
- Haass, Christian
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2020-09-11
- Volume
- 15
- Issue
- 1
- Pages
- 52-52
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC7488484
- OpenAlex
- W3085088911
- Semantic Scholar
- 3c85c2ccd2431e42dd6a3dc5b174ff195152ee65
- Cited by
- 83
- References
- 48
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 14 · 2022: 19 · 2021: 14 · 2020: 2
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- Figshare (cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (390857198)
- Terveyden Tutkimuksen Toimikunta (307866, 315459, 334802)
- H2020 Marie Skłodowska-Curie Actions (740264)
- Academy of Finland (330178)
- 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
- Alzheimer's disease, PLCγ2, microglia, TREM2 signaling, macrophages, phagocytosis, innate immunity, neuroinflammation, knock-in mice, neuroprotection
- MeSH terms
- Alzheimer Disease, Animals, Humans, Macrophages, Mice, Inbred C57BL, Genetic Variation, Microglia, Mice, Phospholipase C gamma, Gene Knock-In Techniques
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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.
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