Audrey Coulon, Florian Rabiller, Mari Takalo, Avishek Roy, Alexandre Pelletier, Henna Martiskainen, Dolores Siedlecki‐Wullich, Nina lannette-Weimann, Nad’a Majerníková, Arthur Grenon, Vance Gao, Anaël Erhardt, Anne Pernodet, Morgane Lemaire, Floriane Limoge, Pauline Walle, Tiago Mendes, Karine Guyot, Célia Lemeu, lukas-iohan carvalho, Ana Raquel Melo de Farias, Marc Hulsman, Chloé Najdek, Alejandra Freire‐Regatillo, Orthis Saha, Philippe Amouyel, Camille Charbonnier, Jean‐François Deleuze, Oriol Dols‐Icardo, Heli Jeskanen, Roosa-Maria Willman, Teemu Kuulasmaa, Mitja Kurki, John Hardy, Sami Heikkinen, Henne Holstege, Petra Mäkinen, Gaël Nicolas, Simon Mead, Michael Wagner, Alfredo Ramı́rez, Tuomas Rauramaa, Aarno Palotie, Rebecca Sims, Hilkka Soininen, John van Swieten, Julie Williams, Céline Bellenguez, Carla Gelle, Erwan Lambert, Marcos R Costa, Julia TCW, Enrico Glaab, Anne‐Marie Ayral, Florie Demiautte, Benjamin Grenier‐Boley, Manon Muntaner, Delphine Eberlé, Séverine Deforges, Joel T. Haas, Devrim Kilinc, Christophe Mulle, Julien Chapuis, Mikko Hiltunen, Julie Dumont, Jean‐Charles Lambert
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. This study demonstrates that downregulation of PLCG2, primarily in neurons, impairs synaptic function and elevates amyloid-β levels and Tau protein phosphorylation.