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. 2024 May 13;21:127. doi: 10.1186/s12974-024-03124-5

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© The Author(s) 2024

Open Access 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 8 — Schematic for Nef EV-mediated oligodendrocyte damage and myelin impairment. Nef is released from extracellular vesicles (EVs) and is internalized by bystander cells in the brain. Nef EVs directly damage oligodendrocytes, compromising their survival or metabolism and impairing myelin integrity. This damage is partially mediated by the downregulation of ABCA1. Additionally, Nef may indirectly harm oligodendrocytes by disrupting ABCA1-mediated cholesterol efflux in astrocytes and microglia. This disruption leads to increased intracellular cholesterol levels, lipid raft formation, activation of inflammasomes, and the secretion of pro-inflammatory cytokines. Inflammation is further exacerbated in microglia during recycling and clearance of myelin debris. In astrocytes, degradation of ABCA1 may hinder the transport of critical cholesterol to oligodendrocytes, further disrupting myelin homeostasis. Image created with BioRender