Neuronal downregulation ofPLCG2impairs synaptic function and elicits Alzheimer disease hallmarks

Abstract

ABSTRACTWe developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may impair synaptic mechanisms in rat primary neuronal cultures. Out of the gene targets identified, we found that shRNA-mediated downregulation ofPlcg2in mouse dentate gyrus neurons consistently impaired dendritic morphology and synaptic function. In human neuronal cultures (hNCs),PLCG2downregulation also impaired synaptic function and was associated with increased levels of Aβ and Tau phosphorylation, potentiallyviathe AKT/GSK3β axis. Very rarePLCG2loss-of-function (LoF) variants were associated with a 10-fold increased AD risk.PLCG2LoF carriers exhibit low mRNA/proteinPLCG2/PLCγ2 levels, consistent with nonsense-mediated mRNA decay mechanisms. Restoring PLCγ2 levels in shPLCG2-hNCs fully reversed the disease-related phenotypes. Our findings indicate that the downregulation of PLCγ2 increases the risk of AD by impairing synaptic function and increasing the levels of Aβ and Tau phosphorylation in neurons.