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PreprintCited by 4Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Non-microglial downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease-related hallmarks

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Coulon, Audrey, Rabiller, Florian, Takalo, Mari, Roy, Avishek, Pelletier, Alexandre, Martiskainen, Henna, Siedlecki-Wullich, Dolores, Lannette-Weimann, Nina +58 more·2024·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2024.04.29.591575PMC PMC13042034
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Abstract

We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out 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 Aβ levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/ PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and increasing the Aβ levels and Tau phosphorylation in neurons.

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  • Rare loss-of-function variants in PLCG2 increase AD risk via nonsense-mediated mRNA decay, suggesting that the degree of enzymatic activity of PLCγ2 is the key determinant of whether PLCG2 variants mediate risk-increasing or protective effects on AD or other diseases.

    “it was recently discovered that rare loss-of-function variants in PLCG2 increase AD risk via nonsense-mediated mRNA decay [15], suggesting that the degree of enzymatic activity of PLCγ2 is the key determinant of whether PLCG2 variants mediate risk-increasing or protective effects on AD or other diseases.”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [15]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • 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 [5]

    The Discussion (page unavailable) describes PLCG2-P522R as a functionally hypermorphic variant, supporting the claim that it potentiates PLCγ2 function. It also reports improved synaptic function and behavior in a mouse model, but does not establish the claimed beneficial effects on microglial function across both in vivo and in vitro models. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Loss-of-function variants in PLCG2 impair synaptic function.

    “Conversely, loss-of-function variants in PLCG2 have been shown to impair synaptic function [5].”

    From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [5]

    The Results section reports that the PLCG2 p.R953* loss-of-function variant significantly decreased synaptic density and burst frequency in human neuronal cultures. Our copy shows a synaptic-function test for that variant, but not for multiple loss-of-function variants; the p.Q816* findings concern reduced PLCG2 expression. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Neuronal downregulation of PLCG2 impairs synaptic function and triggers AD-related alterations.

    “recent findings have revealed that neuronal downregulation of PLCG2 impairs synaptic function and triggers AD-related alterations, suggesting that changes in PLCγ2 levels and subsequent functions also within neurons are significant in the context of AD [5].”

    From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [5]

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Authors
Coulon, A., Rabiller, F., Takalo, M., Roy, A., Pelletier, A., Martiskainen, H., Siedlecki-Wullich, D., Lannette-Weimann, N., Majerníková, N., Grenon, A., Gao, V., Erhardt, A., Pernodet, A., Lemaire, M., Limoge, F., Walle, P., Mendes, T., Guyot, K., Lemeu, C., Carvalho, L.-I., Melo de Farias, A. R., Hulsman, M., Najdek, C., Freire-Regatillo, A., Saha, O., Amouyel, P., Charbonnier, C., Deleuze, J.-F., Dols-Icardo, O., Jeskanen, H., Willman, R.-M., Kuulasmaa, T., Kurki, M., Hardy, J., Heikkinen, S., Holstege, H., Mäkinen, P., Nicolas, G., Mead, S., Wagner, M., Ramirez, A., Rauramaa, T., Palotie, A., Sims, R., Soininen, H., van Swieten, J., Williams, J., Bellenguez, C., Gelle, C., Lambert, E., Costa, M. R., TCW, J., Glaab, E., Ayral, A.-M., Demiautte, F., Grenier-Boley, B., Muntaner, M., Eberlé, D., Deforges, S., Haas, J., Kilinc, D., Mulle, C., Chapuis, J., Hiltunen, M., Dumont, J., & Lambert, J.-C.
Affiliations
  • Inserm (FR)
  • University of Eastern Finland (FI)
  • Centre National de la Recherche Scientifique (FR)
  • Boston University (US)
  • Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France
  • Amsterdam Neuroscience (NL)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
  • University of Helsinki (FI)
  • UCL Queen Square Institute of Neurology (GB)
  • MRC Prion Unit (GB)
  • University of Bonn (DE)
  • Instituto de Salud Carlos III (ES)
  • Cardiff University (GB)
  • Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands
  • UK Dementia Research Institute (GB)
  • F. Hoffmann-La Roche AG (CH)
  • University of Luxembourg (LU)
Corresponding author
  • Dumont, Julie
  • Lambert, Jean-Charles
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2024-05-01
DOI
10.1101/2024.04.29.591575
PMC
PMC13042034
OpenAlex
W4396589334
Cited by
3
References
56
Citations by year
2026: 1 · 2025: 1 · 2024: 1
Type
posted content
Language
en
Open access
Licence
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Alzheimer's Association (AARG-22-926152, ADSF-24-1284326-C)
  • Itä-Suomen Yliopisto
  • Edward N. and Della L. Thome Memorial Foundation
  • Health Resources in Action
  • EU Joint Programme – Neurodegenerative Disease Research (334802)
  • Fondation Vaincre Alzheimer
  • Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
  • European Genomic Institute for Diabetes
  • European Commission
  • Agence Nationale de la Recherche (ANR-21-CE16-0010, ANR-24-CE14-5376, ANR-19-JPW2-0006, 101042759)
  • Institut National de la Santé et de la Recherche Médicale
  • Fonds National de la Recherche Luxembourg
  • Fondation pour la Recherche Médicale (ALZ201912009628)
  • Jane ja Aatos Erkon Säätiö
  • Centre National de la Recherche Scientifique
  • Université de Bordeaux
  • Sigrid Juséliuksen Säätiö (330178, 338182, 355604)
  • UK Dementia Research Institute
  • Fondation pour la Recherche sur Alzheimer
  • Medical Research Council
  • European Regional Development Fund
  • National Institute on Aging (R01AG083941, R01AG082362)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
PLCγ2, Alzheimer's disease, synaptic function, dendritic morphology, amyloid-beta, tau phosphorylation, loss-of-function mutations, neurexin, dentate gyrus neurons, single-nucleus RNA sequencing, high-content screening, genetic risk factors

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