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

Reduced PLCG2 expression impairing dendritic morphology and synaptic function, with increased amyloid-β and Tau phosphorylation; very rare loss-of-function variants are accompanied by low mRNA and protein levels.

The authors developed a high-content screen to test how Alzheimer's disease genetic risk factors affect synaptic mechanisms in rat primary neuronal cultures. Among the target genes identified, Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function; in human neuronal cultures, PLCG2 downregulation likewise impaired synaptic function and increased amyloid-β levels and Tau phosphorylation. Very rare PLCG2 loss-of-function variants were associated with a tenfold increased Alzheimer's disease risk, carriers showing low mRNA and protein levels, and the R953Ter variant compromised synaptic function while increasing disease hallmarks in human cultures. Single-nucleus RNA sequencing confirmed an impact on synaptic and neuronal pathways, potentially through neurexins.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The functional work is solid and shifts PLCG2 from a purely microglial role towards a direct neuronal effect on the synapse, which matters for the credibility of therapeutic targets derived from this gene. Clinically, a tenfold relative risk remains a relative risk: it concerns very rare loss-of-function variants, with no carrier count or family segregation from which penetrance could be derived, so it supports no individual result disclosure in clinic. This belongs with mechanistic data, not with arguments for broadening susceptibility testing.

Analysis by Dr Thibaut Benquey