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

Ramakrishna, S and Jhaveri, V and Konings, SC and Nawalpuri, B and Chakraborty, S and Holst, B and Schmid, B and Gouras, GK and Freude, KK and Muddashetty, RS (2021) Apoe4 affects basal and nmdar-mediated protein synthesis in neurons by perturbing calcium homeostasis. In: Journal of Neuroscience, 41 (42). pp. 8686-8709.

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Official URL: https://doi.org/10.1523/JNEUROSCI.0435-21.2021


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.

Item Type: Journal Article
Publication: Journal of Neuroscience
Publisher: Society for Neuroscience
Additional Information: The copyright for this article belongs to the author.
Keywords: Alzheimer's disease; APOE; Calcium; L-VGCC; NMDAR; Protein synthesis
Department/Centre: Autonomous Societies / Centres > Centre for Brain Research
Date Deposited: 28 Oct 2023 03:03
Last Modified: 28 Oct 2023 03:03
URI: https://eprints.iisc.ac.in/id/eprint/82789

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