Group 1 mGluR stimulation rescues APOE4-mediated translation defects in neurons.

The E4 isoform of apolipoprotein (APOE4) is the most recognized risk factor for Alzheimer's disease, implicated in early neurodegeneration and impaired synaptic plasticity. In neurons, exposure to APOE4 disrupts basal and NMDAR-mediated calcium signaling, further disrupting protein synthesis response. Group 1 mGluRs, a major class of glutamate receptors, also play a critical role in synaptic plasticity through activity-dependent protein synthesis. In this study, we examine neuronal protein synthesis response to mGluR stimulation in the background of APOE4 treatment. In DIV15 primary cortical neurons from Sprague-Dawley rat embryos, exposure to APOE4 induces inhibition of protein synthesis, which is rescued by stimulation of mGluRs for 5 min. mGluR stimulation also rescued the APOE4-induced reduction in synaptic activity as measured by the multi-electrode array. This mGluR-mediated rescue is driven by phosphorylation of RPS6, downstream of the mammalian target of rapamycin (mTOR) pathway as it is abolished by rapamycin treatment. This p-RPS6-driven rescue is independent of calcium-mediated translation inhibition induced by APOE4, demonstrating a specific and independent role of mTORC1 activity in maintaining mGluRs' translation capacity under APOE4 exposure. The potential of mGluR-mediated response to compensate for the effect of APOE4 suggests a dynamic mechanism for the induction of plasticity in human APOE4 carriers. This study provokes a critical need to explore the altered synaptic dynamics in the presence of APOE4 and its impact on cognition.