bioRxiv : the preprint server for biology · 2026

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, Majerníková Nad'a, Grenon Arthur, Gao Vance, Erhardt Anaël, Pernodet Anne, Lemaire Morgane, Limoge Floriane, Walle Pauline, Mendes Tiago, Guyot Karine, Lemeu Célia, Carvalho Lukas-Iohan, de Farias Ana Raquel Melo, Hulsman Marc, Najdek Chloé, Freire-Regatillo Alejandra, Saha Orthis, Amouyel Philippe, Charbonnier Camille, Deleuze Jean-François, Dols-Icardo Orio, Jeskanen Heli, Willman Roosa-Maria, Kuulasmaa Teemu, Kurki Mitja, Hardy John, Heikkinen Sami, Holstege Henne, Mäkinen Petra, Nicolas Gaël, Mead Simon, Wagner Michael, Ramirez Alfredo, Rauramaa Tuomas, Palotie Aarno, Sims Rebecca, Soininen Hilkka, van Swieten John, Williams Julie, Bellenguez Céline, Gelle Carla, Lambert Erwan, Costa Marcos R, Tcw Julia, Glaab Enrico, Ayral Anne-Marie, Demiautte Florie, Grenier-Boley Benjamin, Muntaner Manon, Eberlé Delphine, Deforges Séverine, Haas Joel, Kilinc Devrim, Mulle Christophe, Chapuis Julien, Hiltunen Mikko, Dumont Julie, Lambert Jean-Charles

Аннотация

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.

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

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Аннотация