Journal Article

DZNE-2026-00945

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.

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.DZNE* ; Ramirez, A.DZNE* ; 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. T. ; Kilinc, D. ; Mulle, C. ; Chapuis, J. ; Hiltunen, M. ; Dumont, J. ; Lambert, J.-C.

2026
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-026-02709-5

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.

Keyword(s): Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Animals (MeSH) ; Phospholipase C gamma: genetics (MeSH) ; Phospholipase C gamma: metabolism (MeSH) ; Humans (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Down-Regulation (MeSH) ; Synapses: metabolism (MeSH) ; Synapses: physiology (MeSH) ; Synapses: genetics (MeSH) ; Mice (MeSH) ; tau Proteins: metabolism (MeSH) ; Phosphorylation (MeSH) ; Cells, Cultured (MeSH) ; Rats (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Dentate Gyrus: metabolism (MeSH) ; Phospholipase C gamma ; tau Proteins ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Neuropsychology (AG Wagner)
2. Patient Studies (Bonn) (Patient Studies (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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