PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures

Coulon, Audrey, Rabiller, Florian, Takalo, Mari, Roy, Avishek, Pelletier, Alexandre, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199 and Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259 2026. PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures. Nature Genetics 10.1038/s41588-026-02709-5

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	For full list of authors see article webpage https://doi.org/10.1038/s41588-026-02709-5
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	19 August 2026
Date of Acceptance:	13 July 2026
Last Modified:	19 Aug 2026 09:30
URI:	https://orca.cardiff.ac.uk/id/eprint/189074

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