APOE4 affects basal and nmdar mediated protein synthesis in neurons by perturbing Calcium Homeostasis

Abstract

Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans, APOE2, APOE3, and APOE4. APOE4 is the most well-established genetic risk factor increasing the predisposition for Alzheimer's disease (AD). APOE is involved in clearance of Aβ with APOE4 having the least ability to clear Aβ, hence increasing the risk for AD. Recently, the presence of APOE4 allele alone is shown to cause synaptic defects in neurons and studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4-induced synaptic dysfunction remain elusive. In my thesis, I show that the exposure of neurons to APOE4 leads to a significant decrease in global protein synthesis. I have shown this in rat primary cortical neurons, rat cortical synaptoneurosomes and human iPSC derived neurons. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure of neurons to APOE3 causes a short burst of calcium through NMDA receptors (NMDARs) leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-type voltage-gated calcium channels (L-VGCCs), thereby causing sustained translation inhibition through eukaryotic translation elongation factor 2 (eEF2) phosphorylation. Interestingly, NMDAR stimulation in the background of APOE4 treatment leads to stress response, causing an increase in phosphorylation of eukaryotic translation initiation factor (eIF2α) as well. Along with basal protein synthesis, APOE4 treatment also abrogates the NMDA-mediated translation response indicating an alteration of synaptic signaling. Thus, we show that APOE4 affects basal and activity-mediated protein synthesis responses in neurons by affecting calcium homeostasis.