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

Coulon A(#)(1), Rabiller F(#)(1), Takalo M(#)(2), Roy A(#)(3), Pelletier
A(#)(4), Martiskainen H(#)(2), Siedlecki-Wullich D(1), Lannette-Weimann N(1),
Majerníková N(1), Grenon A(5), Gao V(1), Erhardt A(3), Pernodet A(1), Lemaire
M(1), Limoge F(1), Walle P(1), Mendes T(1), Guyot K(1), Lemeu C(1), Carvalho
LI(1), Melo de Farias AR(1), Hulsman M(6)(7)(8), Najdek C(1), Freire-Regatillo
A(1), Saha O(1), Amouyel P(1), Charbonnier C(9), Deleuze JF(10), Dols-Icardo
O(11)(12), Jeskanen H(2), Willman RM(2), Kuulasmaa T(2), Kurki M(13), Hardy
J(14), Heikkinen S(2), Holstege H(6)(7)(8), Mäkinen P(2), Nicolas G(15), Mead
S(16), Wagner M(17)(18), Ramirez A(17)(18)(19)(20)(21), Rauramaa T(22), Palotie
A(12), Sims R(23), Soininen H(24), van Swieten J(25), Williams J(26), Bellenguez
C(1), Gelle C(1), Lambert E(1), Costa MR(1)(27)(28), Tcw J(4)(29), Glaab E(30),
Ayral AM(1), Demiautte F(1), Grenier-Boley B(1), Muntaner M(1), Eberlé D(5),
Deforges S(3), Haas JT(5), Kilinc D(1), Mulle C(3), Chapuis J(1), Hiltunen M(2),
Dumont J(31), Lambert JC(32).

Author information:
(1)Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE,
Lille, France.
(2)Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
(3)Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of
Bordeaux, Bordeaux, France.
(4)Department of Pharmacology, Physiology & Biophysics, Boston University
Chobanian & Avedisian School of Medicine, Boston, MA, USA.
(5)Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, EGID-U1011, Lille,
France.
(6)Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije
Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
(7)Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam,
Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
(8)Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
(9)Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of
Biostatistics and CNRMAJ, Rouen, France.
(10)Commissariat à L’Énergie Atomique et Aux Énergies Alternatives, Centre
National de Recherche en Génomique Humaine, Université Paris-Saclay,
Gif-sur-Yvette, France.
(11)Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant
Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
(12)Biomedical Research Networking Center on Neurodegenerative Diseases,
National Institute of Health Carlos III, Madrid, Spain.
(13)Institute for Molecular Medicine Finland, University of Helsinki, Helsinki,
Finland.
(14)Reta Lila Weston Research Laboratories, Department of Molecular
Neuroscience, University College London Institute of Neurology, London, UK.
(15)Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics
and CNRMAJ, Rouen, France.
(16)Medical Research Council Prion Unit, University College London Institute of
Prion Diseases, London, UK.
(17)Department of Cognitive Disorders and Old Age Psychiatry, Medical Faculty,
University Hospital Bonn, Bonn, Germany.
(18)German Center for Neurodegenerative Diseases, Bonn, Germany.
(19)Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry
and Psychotherapy, Faculty of Medicine and University Hospital Cologne,
University of Cologne, Cologne, Germany.
(20)Department of Psychiatry, Glenn Biggs Institute for Alzheimer’s &
Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
(21)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated
Disease (CECAD), University of Cologne, Cologne, Germany.
(22)Department of Pathology, Kuopio University Hospital, Kuopio, Finland and
Unit of Pathology, Institute of Clinical Medicine, University of Eastern
Finland, Kuopio, Finland.
(23)Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,
Division of Psychological Medicine and Clinical Neuroscience, School of
Medicine, Cardiff University, Cardiff, UK.
(24)Department of Neurology, University of Eastern Finland, Kuopio, Finland.
(25)Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.
(26)UK Dementia Research Institute and Moondance Dementia Research Laboratory,
Department of Psychological Medicine, Cardiff University, Cardiff, UK.
(27)Roche Pharma Research and Early Development, Neuroscience and Rare Diseases,
Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
(28)Brain Institute, Federal University of Rio Grande do Norte, Natal, Brazil.
(29)Bioinformatics Program, Faculty of Computing & Data Sciences, Boston
University, Boston, MA, USA.
(30)Luxembourg Centre for Systems Biomedicine, University of Luxembourg,
Esch-sur-Alzette, Luxembourg.
(31)Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE,
Lille, France. .
(32)Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE,
Lille, France. .
(#)Contributed equally

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.

© 2026. The Author(s).

DOI: 10.1038/s41588-026-02709-5
PMID: 42601455

Conflict of interest statement: Competing interests: M.R.C. is an employee of
Roche. The remaining authors declare no competing interests.

Auteurs Bordeaux Neurocampus