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[220923 저널발표] Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

한지희 │ 2022-09-21

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https://doi.org/10.1016/j.stem.2022.07.005


Cell Stem Cell
Volume 29, Issue 8, 4 August 2022, Pages 1197-1212.e8
Journal home page for Cell Stem Cell

Article
Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

https://doi.org/10.1016/j.stem.2022.07.005Get rights and content
Referred to by
Jessica E. Young, Suman Jayadev
Neighborhood matters: Altered lipid metabolism in APOE4 microglia causes problems for neurons
Cell Stem Cell, Volume 29, Issue 8, 4 August 2022, Pages 1159-1160
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Highlights

Microglia-like cells (iMGLs) respond to soluble factors secreted by neurons

APOE4 renders iMGLs weakly responsive to neuronal activity

APOE4 iMGLs disrupts the coordinated activity of neuronal ensembles

Microglial lipid homeostasis is critical to sustain surveillance states

Summary

Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer’s disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer’s disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.

Keywords

stem cells
microglia
forebrain spheroids
lipid droplet
network-activity
calcium dynamics
APOE
Alzheimer’s risk variant
GIRKs



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