{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T12:45:48Z","timestamp":1774961148893,"version":"3.50.1"},"posted":{"date-parts":[[2024,5,1]]},"group-title":"Neuroscience","reference-count":89,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>Plcg2<\/jats:italic>\n                  downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs),\n                  <jats:italic>PLCG2<\/jats:italic>\n                  downregulation also impaired synaptic function and increased A\u03b2 levels and Tau phosphorylation. Very rare\n                  <jats:italic>PLCG2<\/jats:italic>\n                  loss-of-function (LoF) variants were associated with a 10-fold increased AD risk.\n                  <jats:italic>PLCG2<\/jats:italic>\n                  LoF carriers exhibit low mRNA\/protein\n                  <jats:italic>PLCG2\/<\/jats:italic>\n                  PLC\u03b32 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of\n                  <jats:italic>PLCG2<\/jats:italic>\n                  impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLC\u03b32 downregulation could increase AD risk by impairing synaptic functions and increasing the A\u03b2 levels and Tau phosphorylation in neurons.\n                <\/jats:p>","DOI":"10.1101\/2024.04.29.591575","type":"posted-content","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T21:55:18Z","timestamp":1714600518000},"source":"Crossref","is-referenced-by-count":3,"title":["Non-microglial downregulation of\n                  <i>PLCG2<\/i>\n                  impairs synaptic function and elicits Alzheimer disease-related hallmarks"],"prefix":"10.64898","author":[{"given":"Audrey","family":"Coulon","sequence":"first","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et d\u00e9terminants mol\u00e9culaires des maladies li\u00e9es au vieillissement, Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Rabiller","sequence":"additional","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et d\u00e9terminants mol\u00e9culaires des maladies li\u00e9es au vieillissement, Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Takalo","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avishek","family":"Roy","sequence":"additional","affiliation":[{"name":"Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Pelletier","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henna","family":"Martiskainen","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dolores","family":"Siedlecki-Wullich","sequence":"additional","affiliation":[{"name":"Univ. 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