TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.
Neuron, 2020/03/04;105(5):837-854.e9.
Nugent AA[1], Lin K[1], van Lengerich B[1], Lianoglou S[1], Przybyla L[1], Davis SS[1], Llapashtica C[1], Wang J[1], Kim DJ[1], Xia D[1], Lucas A[1], Baskaran S[1], Haddick PCG[1], Lenser M[1], Earr TK[1], Shi J[1], Dugas JC[1], Andreone BJ[1], Logan T[1], Solanoy HO[1], Chen H[1], Srivastava A[1], Poda SB[1], Sanchez PE[1], Watts RJ[1], Sandmann T[1], Astarita G[1], Lewcock JW[1], Monroe KM[2], Di Paolo G[3]
Affiliations
PMID: 31902528DOI: 10.1016/j.neuron.2019.12.007
Impact factor: 18.688
Abstract
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.
Keywords: APOE; Alzheimer’s disease; TREM2; cholesterol; cholesteryl ester; lipid metabolism; microglia; myelin; neurodegeneration; phagocytosis
MeSH terms
Acetyl-CoA C-Acetyltransferase; Alzheimer Disease; Animals; Brain; Cholesterol; Cholesterol Esters; Disease Models, Animal; Flow Cytometry; Humans; Induced Pluripotent Stem Cells; Lipid Metabolism; Lipidomics; Liver X Receptors; Macrophages; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Knockout, ApoE; Microglia; Myelin Sheath; Phagocytosis; RNA-Seq; Receptors, Immunologic
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