ArticleMolecular neurodegeneration2020
The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes immune functions.
Article in Molecular neurodegeneration, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 81 citations in OpenAlex.
- PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.Nature genetics · 2026Article
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- PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.bioRxiv : the preprint server for biology · 2026Article
- Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging.Journal of molecular biology · 2026Review
- Therapeutic targeting of neuroimmune mechanisms in neurodegeneration.Nature reviews. Drug discovery · 2026Review
- Non-microglial downregulation ofbioRxiv : the preprint server for biology · 2026Article
- PLCG2 signaling and genetic resilience in Alzheimer's disease.Molecular neurodegeneration · 2026Review
- Conserved Pathways, Divergent Outcomes: A Cross-Species Genomic Perspective on the Cancer-Neurodegeneration Paradox.International journal of molecular sciences · 2026Review
- Immune dysfunction in Alzheimer disease.Nature reviews. Neuroscience · 2026Review
- Protective PLCG2 variants associate with a delayed onset of Alzheimer's disease among heterozygous APOE ε4 carriers.Alzheimer's research & therapy · 2026Article
- Genetics of PLCG2 expression and splicing relative to Alzheimer's disease risk.Molecular neurodegeneration advances · 2026Article
- Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- TREM2 Modulates Postoperative Cognitive Function in Aged Mice by Inhibiting the NLRP3/caspase-1 Pathway and Apoptosis via PLCγ2 Activation.Molecular neurobiology · 2025Article
- PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- A high-throughput assay platform to discover small molecule activators of the phospholipase PLC-γ2 to treat Alzheimer's disease.The Journal of biological chemistry · 2025Article
- The protective PLCγ2-P522R variant mitigates Alzheimer's disease-associated pathologies by enhancing beneficial microglial functions.Journal of neuroinflammation · 2025Article
- CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.Frontiers in neurology · 2025Review
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- The crystal and cryo-EM structures of PLCγ2 reveal dynamic interdomain recognitions in autoinhibition.Science advances · 2024Article
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMicroglia-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.
methodsTo 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.
resultsFunctional 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.
conclusionThe 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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