Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is closely linked to genetic factors that affect lipid metabolism, particularly in microglial cells—the brain’s immune cells. Emerging evidence suggests that genetic factors like the APOE4 variant, a major risk factor for AD, may disrupt lipid processing in microglia, leading to various cellular states that affect or may exacerbate neurodegeneration. Using single-nucleus RNA sequencing on frozen postmortem human AD brain tissue with the APOE4/4 genotype, microglia characterized by the expression of the enzyme ACSL1 have been identified to be associated with increased lipid droplet accumulation and subsequent neurotoxicity.
In a 2024 publication in Nature Communications, Haney et al. discovered that in lab-grown microglia, exposure to amyloid-beta (Aβ) triggered ACSL1 expression, leading to triglyceride production and lipid droplet accumulation, in an APOE4/4-dependent manner. Lipid droplets were stained with Biotium’s LipidSpot™ 488 to visualize changes in lipid droplet formation in APOE4/4 human induced pluripotent stem (iPS) cells with and without fibrillar Aβ treatment and in primary rat microglia treated with fibrillar Aβ. In immunofluorescence experiments of brain tissue, LipidSpot™ 488 shows more lipid body positive microglia in APOE deficient mouse models (Fig. A, B), and in neurons treated with lipid droplet accumulating microglia (LDAM)-specific conditioned media.
The authors propose that the APOE4/4 genotype in AD patients increases ACSL1 expression and lipid droplet accumulation in microglia, which leads to a pro-inflammatory state and impaired phagocytic function. These lipid-loaded microglia release factors that induce Tau protein phosphorylation and neurotoxicity, suggesting that genetic risk factors like APOE4 may promote harmful lipid accumulation in microglia contributing to AD progression. Understanding the role of lipid metabolism in microglia offers new insights into the mechanisms underlying Alzheimer’s disease and presents potential targets for therapeutic intervention, particularly in individuals with the APOE4/4 genotype.
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Full Citation:
Haney, M.S., Pálovics, R., Munson, C.N. et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature 628, 154–161 (2024). https://doi.org/10.1038/s41586-024-07185-7