APOE4 Affects Basal and NMDAR-Mediated Protein Synthesis in Neurons by Perturbing Calcium Homeostasis

• DOI: 10.1523/jneurosci.0435-21.2021
• Publication Date: 2021-09-02T17:50:44Z
• Authors: Sarayu Ramakrishna; Vishwaja Jhaveri; Sabine C. Konings; Bharti Nawalpuri; Sumita Chakraborty; Bjørn Holst; Benjamin Schmid; Gunnar K. Gouras; Kristine K. Freude; Ravi S. Muddashetty
• Keywords: Homeostasis; Basal (medicine)

Apolipoprotein E (APOE), one of the primary lipoproteins in brain has three isoforms humans, APOE2, APOE3, and APOE4. APOE4 is most well-established risk factor increasing predisposition for Alzheimer's disease (AD). The presence allele alone shown to cause synaptic defects neurons recent studies have identified multiple pathways directly influenced by However, mechanisms underlying APOE4-induced dysfunction remain elusive. Here, we report that acute exposure cortical or synaptoneurosomes leads a significant decrease global protein synthesis. Primary were derived from male female embryos Sprague Dawley (SD) rats C57BL/6J mice. Synaptoneurosomes prepared P30 SD rats. treatment also abrogates NMDA-mediated translation response indicating an alteration signaling. Importantly, demonstrate both APOE3 generate distinct which closely linked their respective calcium signature. Acute causes short burst through NMDA receptors (NMDARs) leading initial synthesis quickly recovers. Contrarily, sustained increase levels activating NMDARs L-type voltage-gated channels (L-VGCCs), thereby causing inhibition eukaryotic elongation 2 (eEF2) phosphorylation, turn disrupts NMDAR response. Thus, show affects basal activity-mediated responses affecting homeostasis.SIGNIFICANCE STATEMENT Defective been as early defect familial this not studied context sporadic AD, constitutes majority cases. In our study, E4 (APOE4), predominant inhibits neurons. response, thus inhibiting translation. We defective mediated perturbation homeostasis caused propose dysregulation possible molecular explain APOE4-mediated cognitive defects. Hence, study only suggests explanation it bridges gap understanding pathology.