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IDENTIFYING A NEURONAL ROLE FOR THE GENETIC RISK FACTOR <EM>PLCG2</EM> IN ALZHEIMER’S DISEASE
Audrey Coulonand 25 co-authors
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-211
Presentation
Date TBA
Board: PS05-09AM-211
Event Information
Poster Board
PS05-09AM-211
Poster
View posterAbstract
Based on the new genetic landscape of Alzheimer’s disease (AD), we and others proposed that synaptic fragility/sensitivity is a pathological trigger, depending on genetic risk factors. Some of these factors have already been linked to synaptic mechanisms, including BIN1, FERMT2, PTK2B and CD2AP. Within this context, we systematically investigated the potential implications of the genes located in the loci associated with AD risk at synapses. We developed a high content screening to investigate how genetic risk factors for AD may impact synaptic density and function in rat primary neuronal cultures. One of the best hits was the PLCG2 gene. Although PLCG2 has been extensively studied in microglia where it influences the clearance of amyloid plaques, our data suggested that this gene also plays a role at synapses. Consistent impairment of dendritic morphology and synaptic function was found in Plcg2-downregulated mouse dentate gyrus neurons. Genetically, the PLCG2 P522R variant confers protection against AD and is hypermorphic, whereas loss-of-function variants are associated with a 10-fold increase in AD risk. In line with these findings, downregulation of PLCG2 in human induced pluripotent stem cells-derived neurons (hiNs) damaged synapses and increased the levels of Aβ and abnormally phosphorylated Tau. Single-nucleus RNA sequencing and immunoblotting in hiNs confirmed that PLCG2 downregulation impacts pathways related to synaptic and neuronal functions, potentially through neurexins and GSK3β. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic function and increasing the levels of Aβ and abnormally phosphorylated Tau in neurons.
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