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[200110 저널발표] TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge

이동준 │ 2020-01-15

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https://doi.org/10.1016/j.neuron.2019.12.007


Neuron
Available online 2 January 2020
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Article
TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge

Highlights

Upon demyelination, Trem2–/– microglia fail to upregulate lipid metabolism genes

Trem2–/– microglia accumulate cholesteryl ester derived from myelin cholesterol

Accumulation is rescued by ACAT1 inhibitor and LXR agonist

Apoe–/– glia defective in cholesterol transport also accumulate cholesteryl ester

Summary

Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer’s disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase is also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding replicates in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it is rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia.




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