ArticleAlzheimer's research & therapy2019
Alzheimer's disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph.
Article in Alzheimer's research & therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 1 of them a synthesis that pooled it.
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Who cites it
91 citing papers in PubMed, 1 synthesis or guideline pooled it, 143 citations in OpenAlex.
- Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer's Disease Genetics.Trends in neurosciences · 2020Pooled it
- Biobank-based genetic characterization of neurodegenerative diseases and idiopathic normal pressure hydrocephalus: insights and lessons learned from FinnGen.Molecular psychiatry · 2026Review
- PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.Nature genetics · 2026Article
- Article
- 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
- Are we fully exploiting genetic discoveries to understand and treat Alzheimer's disease?Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Non-microglial downregulation ofbioRxiv : the preprint server for biology · 2026Article
- PLCG2 signaling and genetic resilience in Alzheimer's disease.Molecular neurodegeneration · 2026Review
- Salutogenomics: embracing the full spectrum of human health.Trends in genetics : TIG · 2026Review
- Immune dysfunction in Alzheimer disease.Nature reviews. Neuroscience · 2026Review
- Systems biology of Alzheimer's Disease: a scoping review of key pathways and mechanisms.Molecular neurodegeneration · 2026Article
- Identification of genes associated with smell dysfunction in Parkinson's disease.Clinical parkinsonism & related disorders · 2026Article
- Genetics of PLCG2 expression and splicing relative to Alzheimer's disease risk.Molecular neurodegeneration advances · 2026Article
- Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways.Molecular neurodegeneration · 2025Article
- 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
- Protective genetic variants against Alzheimer's disease.The Lancet. Neurology · 2025Review
- 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
- Fokker-Planck diffusion maps of microglial transcriptomes reveal radial differentiation into substates associated with Alzheimer's pathology.Communications biology · 2025Article
31 more citing papers are in PubMed but not listed here.
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12 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundRecent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer's disease (LOAD). Amongst these, a polymorphism in phospholipase C-gamma 2 (PLCG2) P522R has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.
methodsWe assessed PLCG2 distribution in human and mouse brain tissue via immunohistochemistry and in situ hybridization. We transfected heterologous cell systems (COS7 and HEK293T cells) to determine the effect of the P522R AD-associated variant on enzymatic function using various orthogonal assays, including a radioactive assay, IP-One ELISA, and calcium assays.
resultsPLCG2 expression is restricted primarily to microglia and granule cells of the dentate gyrus. Plcg2 mRNA is maintained in plaque-associated microglia in the cerebral tissue of an AD mouse model. Functional analysis of the p.P522R variant demonstrated a small hypermorphic effect of the mutation on enzyme function.
conclusionsThe PLCG2 P522R variant is protective against AD. We show that PLCG2 is expressed in brain microglia, and the p.P522R polymorphism weakly increases enzyme function. These data suggest that activation of PLCγ2 and not inhibition could be therapeutically beneficial in AD. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.