TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge

Nugent, Alicia A.; Lin, Karin; Lengerich, Bettina van; Lianoglou, Steve; Przybyla, Laralynne; Davis, Sonnet S.; Llapashtica, Ceyda; Wang, Junhua; Kim, Dojin; Xia, Dan; Lucas, Anthony; Baskaran, Sulochanadevi; Haddick, Patrick C.G.; Lenser, Melina; Earr, Timothy; Ju, Shaoqing; Dugas, Jason C.; Andreone, Benjamin J.; Logan, Todd; Solanoy, Hilda; Chen, Hang; Srivastava, Ankita; Poda, Suresh B.; Sanchez, Pascal; Watts, Ryan J.; Sandmann, Thomas; Astarita, Giuseppe; Lewcock, Joseph W.; Monroe, Kathryn M.; Paolo, Gilbert Di

doi:10.1016/j.neuron.2019.12.007

Cited by 407 publications

(346 citation statements)

References 88 publications

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“…By mediating phagocytosis of dying adipocytes TREM2-positive LAMs control adipose tissue adaptation to obesity. In contrast, loss of TREM2 prevents LAM formation causing adipocyte hypertrophy, weight gain, and insulin resistance.TREM2 is a transmembrane receptor of the immunoglobulin superfamily binding anionic ligands such as bacterial LPS, phospholipids, (apo)lipoproteins and cholesterol-containing myelin fragments[8][9][10][11].…”

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confidence: 99%

TREM2-Positive Lipid-Associated Macrophages (LAMs) Control White Adipose Tissue Remodeling and Metabolic Adaptation in Obesity

Worthmann¹,

Heeren²

2020

Immunometabolism

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White adipose tissue (WAT) depots are populated with a large range of immune cells under both normal and obese conditions. During the progression of obesity, these immune cells increase in total abundance and in particular macrophage subpopulations change dramatically. However, origin, characteristics, and functions of adipose tissue macrophages in obesity are poorly understood. In a recent publication, Jaitin et al. develop an immune cell atlas of obese fat and identify a subclass of triggering receptor expressed on myeloid cells 2 (TREM2)positive, so called lipid-associated macrophages (LAMs) which are critical determinants of adipose tissue homeostasis.

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confidence: 99%

TREM2-Positive Lipid-Associated Macrophages (LAMs) Control White Adipose Tissue Remodeling and Metabolic Adaptation in Obesity

Worthmann¹,

Heeren²

2020

Immunometabolism

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“…Whereas pathogenic missense PLOSL variants affect protein folding and stability, decreasing TREM2 surface localization, R47H, and other AD-associated mutations alter the ligand-binding interface of TREM2 (54,55). Analysis of TREM2 R47H function in human and mouse reporter cells showed impaired recognition of certain anionic lipid ligands (20,56). These findings are interpreted as a weakened function not compensated by the normal allele (haploinsufficiency).…”

Section: Discussionmentioning

confidence: 98%

Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer’s Disease Brain

et al. 2020

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The R47H variant in the microglial triggering receptor expressed on myeloid cell 2 (TREM2) receptor is a strong risk factor for Alzheimer's disease (AD). To characterize processes affected by R47H, we performed an integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant, and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), systemic disease with early-onset dementia caused by loss-of-function mutations in TREM2 or its adaptor TYRO protein tyrosine kinase-binding protein (TYROBP). Although sporadic AD had few perturbed microglial and immune genes, TREM2 R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion, and phagocytosis. TREM2 knockout (KO) in THP1, a human myeloid cell line that constitutively expresses the TREM2-TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C) and phagocytosis of amyloid-beta oligomers; overexpression of ectopic TREM2 restored these functions. Compared with wild-type protein, R47H TREM2 had a higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the TREM2 receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H TREM2 to AD pathology.

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“…TREM2 contributes to this process by sensing lipids and phagocytosing myelin debris. In the absence of TREM2 in mouse models of demyelination, microglia take up myelin debris but fail to degrade it, resulting in the accumulation of lipids and persistent demyelination [ 49 , 50 ]. With aging, Trem2 T66M mice exhibit reduced microglial activity and microglial clusters in white matter tracts [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

Jadhav

Lin

Pennington

et al. 2020

Mol Neurodegeneration

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Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

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TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge

Cited by 407 publications

References 88 publications

TREM2-Positive Lipid-Associated Macrophages (LAMs) Control White Adipose Tissue Remodeling and Metabolic Adaptation in Obesity

TREM2-Positive Lipid-Associated Macrophages (LAMs) Control White Adipose Tissue Remodeling and Metabolic Adaptation in Obesity

Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer’s Disease Brain

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

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