Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4

作者：Georgia L. Nolt, Lesley R. Golden, Shealee P. Thorpe, Jessica L. Funnell, Isaiah O. Stephens, Gabriela Hernandez, Steven M. MacLean, Chloe C. Lucido, Chesney R. Brock, Akhil V. Pallerla, Darcy R. Adreon, Holden C. Williams, Josh M. Morganti, Lance A. Johnson · 发表于：Journal of Neuroinflammation · 年份：2025 · DOI：10.1186/s12974-025-03639-5 · 被引用次数：3 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurogenesis and neuroplasticity mechanisms、Alzheimer's disease research and treatments

Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement sig...