Apoe4 affects basal and nmdar-mediated protein synthesis in neurons by perturbing calcium homeostasis

Sarayu Ramakrishna, Vishwaja Jhaveri, Sabine C. Konings, Bharti Nawalpuri, Sumita Chakraborty, Bjørn Holst, Benjamin Schmid, Gunnar K. Gouras, Kristine K. Freude, Ravi S. Muddashetty

Research output: Contribution to JournalArticleAcademicpeer-review

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 risk factor increasing the predisposition for Alzheimer's disease (AD). The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4-induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague Dawley (SD) rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male SD rats. APOE4 treatment also abrogates the NMDA-mediated translation response indicating an alteration of synaptic signaling. 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 (LVGCCs), thereby causing sustained translation inhibition through eukaryotic translation elongation factor 2 (eEF2) phosphorylation, which in turn disrupts the NMDAR response. Thus, we show that APOE4 affects basal and activity-mediated protein synthesis responses in neurons by affecting calcium homeostasis.
Original languageEnglish
Pages (from-to)8686-8709
JournalJournal of Neuroscience
Volume41
Issue number42
DOIs
Publication statusPublished - 20 Oct 2021
Externally publishedYes

Funding

This work was supported by the NeuroStem Grant BT/IN/Denmark/07/RSM/2015-2016. S.R. was supported by the Junior/Senior Research Fellowship DBT/2016/InStem/540 from the Department of Biotechnology (DBT). G.K.G. was supported by the EU H2020 Marie Sklodowska–Curie Grant 721802 (SYNDEGEN) and the Swedish Research Council Grant 2019-01125. S.C.K. was supported by the EU H2020 Marie Sklodowska–Curie Grant 721802 (SYNDEGEN). We thank all the central facilities at NCBS-inStem, especially the Central Imaging and Flow Cytometry Facility (CIFF), Animal House Facility, and Stem Cell Facility; our collaborators and colleagues for their invaluable suggestions and discussions; specially Dr. Sumantra Chattarji and his lab members from National Center for Biological Sciences, Bangalore, for all the technical help and conceptual scientific discussions; Dr. James Chelliah from JNCASR, Bangalore, for giving us MK801; and thank Dr. Vijayalakshmi Ravindranath and Dr. Reddy P. Kommaddi from Centre for Brain Research, Bangalore, for their generous gift of MAP2 antibody and B27 during the revision experiments. The authors declare no competing financial interests. Correspondence should be addressed to Ravi S. Muddashetty at [email protected] or [email protected]. https://doi.org/10.1523/JNEUROSCI.0435-21.2021 Copyright © 2021 the authors

FundersFunder number
EU H2020 Marie Sklodowska721802
Department of Biotechnology, Ministry of Science and Technology, India
Vetenskapsrådet2019-01125

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