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Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice

Miranda, AM; Ashok, A; Chan, RB; Zhou, B; Xu, Y; McIntire, LB; Area-Gomez, E; ... Nuriel, T; + view all (2022) Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice. Translational psychiatry , 12 (1) , Article 129. 10.1038/s41398-022-01881-6. Green open access

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Abstract

Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for the late-onset form of Alzheimer's disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14-15 month-old APOE3/3, APOE3/4, and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4-associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology.

Type: Article
Title: Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41398-022-01881-6
Publisher version: https://doi.org/10.1038/s41398-022-01881-6
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Amyloid beta-Peptides, Animals, Apolipoprotein E3, Apolipoprotein E4, Entorhinal Cortex, Gene Dosage, Lipidomics, Mice
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10146771
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