{
  "abstract": "We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.",
  "abstract_shown": true,
  "affiliations": [
    "Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France",
    "Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland",
    "Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France",
    "Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA",
    "Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, EGID-U1011, Lille, France",
    "Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands",
    "Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands",
    "Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands",
    "Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Biostatistics and CNRMAJ, Rouen, France",
    "Commissariat à L'Énergie Atomique et Aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, Gif-sur-Yvette, France",
    "Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain",
    "Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain",
    "Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland",
    "Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK",
    "Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France",
    "Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK",
    "Department of Cognitive Disorders and Old Age Psychiatry, Medical Faculty, University Hospital Bonn, Bonn, Germany",
    "German Center for Neurodegenerative Diseases, Bonn, Germany",
    "Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany",
    "Department of Psychiatry, Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA",
    "Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany",
    "Department of Pathology, Kuopio University Hospital, Kuopio, Finland and Unit of Pathology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland",
    "Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK",
    "Department of Neurology, University of Eastern Finland, Kuopio, Finland",
    "Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands",
    "UK Dementia Research Institute and Moondance Dementia Research Laboratory, Department of Psychological Medicine, Cardiff University, Cardiff, UK",
    "Brain Institute, Federal University of Rio Grande do Norte, Natal, Brazil",
    "Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland",
    "Bioinformatics Program, Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA",
    "Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 66,
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      "name": "Audrey Coulon",
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      "name": "Heli Jeskanen",
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      "name": "Henne H. Holstege",
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      "name": "Tuomas H. Rauramaa",
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      "name": "Aarno V. Palotie",
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      "name": "John Cornelis Van Swieten",
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      "name": "Céline Bellenguez",
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      "orcid": "0000-0002-5242-5364"
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      "orcid": "0000-0001-7450-6897"
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      "orcid": "0000-0002-0028-5988"
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  "bibtex": "https://research.draconitic.com/paper/dejd7xa26amt6.bib",
  "cited_by": 5,
  "doi": "10.1038/s41588-026-02709-5",
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  "id": "dejd7xa26amt6",
  "issns": [
    "1061-4036",
    "1546-1718"
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  "landing_url": "https://hal.science/hal-05776225v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
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  "pdf_url": "https://www.nature.com/articles/s41588-026-02709-5.pdf",
  "pmcid": "PMC13042034",
  "pmid": "41928929",
  "published": "2026-08-14",
  "publisher": "Nature Publishing Group",
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      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
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  "title": "PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures",
  "title_text": "PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:49Z",
  "url": "https://research.draconitic.com/paper/dejd7xa26amt6",
  "venue": "Nature Genetics",
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