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ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer’s Disease via Epigenetic Reprogramming of the Asxl1/LXRα–H3K4me3 Axis
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ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer’s Disease via Epigenetic Reprogramming of the Asxl1/LXRα–H3K4me3 Axis
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ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer’s Disease via Epigenetic Reprogramming of the Asxl1/LXRα–H3K4me3 Axis
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Journal Article
ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer’s Disease via Epigenetic Reprogramming of the Asxl1/LXRα–H3K4me3 Axis
2026
Overview
Background
The
ε4
allele of apolipoprotein E gene (
APOE
) stands as the greatest genetic risk factor for late-onset Alzheimer’s disease (AD). Although microglia accumulating lipid droplets (LDAM) have been implicated in AD pathogenesis, the mechanistic link between ApoE4 and microglial lipid dysregulation remains elusive.
Methods
We employed a multi-omics approach, combining snRNA-seq and locus-specific epigenetic analysis, alongside microglia-specific gene manipulation in ApoE-targeted replacement (TR) mice. Primary microglia were challenged with cholesterol to simulate lipid overload conditions.
Results
In mid-life ApoE4-TR mice, microglia within the dentate gyrus developed pronounced lipid droplet accumulation, concurrent with impaired Aβ clearance and a pro-inflammatory shift. snRNA-seq unveiled a unique microglial cluster in ApoE4 mice, enriched for lipid-metabolism genes and marked by the pronounced downregulation of the hub gene Asxl1. Mechanistically, ApoE4 attenuated the Asxl1–LXRα interaction, leading to reduced H3K4me3 occupancy at promoters of lipid-efflux genes such as Abca1. Crucially, CRISPR-mediated, microglia-specific overexpression of Asxl1 restored H3K4me3 levels, normalized cholesterol efflux, and rescued Aβ phagocytic deficits in vivo.
Conclusions
Our findings define an epigenetic pathway whereby ApoE4 drives microglial dysfunction via the Asxl1–LXRα–H3K4me3 axis, fostering the LDAM phenotype. Enhancing Asxl1 function presents a promising therapeutic avenue for countering ApoE4-mediated pathogenesis in AD.
Publisher
BioMed Central,Springer Nature B.V,BMC
Subject
/ Age
/ Alzheimer Disease - genetics
/ Alzheimer Disease - metabolism
/ Alzheimer Disease - pathology
/ Amyloid beta-Peptides - metabolism
/ Animals
/ ApoE4
/ Apolipoprotein E4 - genetics
/ Apolipoprotein E4 - metabolism
/ Asxl1
/ Biomedical and Life Sciences
/ Brain
/ CRISPR
/ Epigenesis, Genetic - physiology
/ Lipid Metabolism - physiology
/ Lipids
/ Liver X Receptors - genetics
/ Liver X Receptors - metabolism
/ Mice
/ Repressor Proteins - genetics
/ Repressor Proteins - metabolism
/ snRNA
