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.

doi:10.2139/ssrn.3444596

Cited by 31 publications

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“…Studies from multiple groups have recently improved our understanding of microglial function in disease and how it is impacted by genetic risk factors. Notably, lipid metabolism, storage, and processing has emerged as a potentially important contributor to proper microglial function in the CNS (Chan et al, 2012;Wang et al, 2015;Keren-Shaul et al, 2017;Griciuc et al, 2019;Marschallinger et al, 2020;Nugent et al, 2019). This may indicate that TREM2-stimulating therapeutic approaches could be employed in a variety of different clinical syndromes including AD, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, retinal degeneration, multiple sclerosis, and obesity-associated metabolic syndromes.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with these observations, TREM2 appears to be required for elimination of damaged myelin by microglia (Cantoni et al , ). Moreover, TREM2‐deficient microglia were shown to be overloaded with cholesterol esters (CEs) as well as other lipid species as a result of chronic phagocytic challenge of myelin debris induced by a cuprizone diet (Nugent et al , ), indicating that TREM2 is important for lipid processing in addition to phagocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

et al. 2020

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Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

et al. 2020

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“…These results provide evidence that AD risk alleles burden regulatory sequences similarly across all three myeloid cell types and that the basal state is, at least in part, relevant to the study of regulatory variants that affect AD risk. Recent findings that TREM2 loss of function similarly impacts the response of both central nervous system (CNS) and peripheral macrophages to lipid overload [69][70][71] and that the activation state of human macrophages does not have a major impact on AD heritability enrichment 72 could indicate that Alzheimer's disease-associated variants might regulate core functions of the macrophage lineage (e.g., the phagocytic clearance of apoptotic cells and other lipidrich cellular debris). These results highlight the need to generate additional large-scale human microglial/myeloid epigenomic and transcriptomic datasets (e.g., in the context of immune and metabolic stress) which will enable identification of the most disease-relevant myeloid cell states and enable replication and extension of our findings.…”

Section: Locusmentioning

confidence: 99%

Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes

et al. 2021

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Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.

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“…Emerging evidence suggest that TREM2 is essential for disease associated microglia (DAM) [33,34] and microglial neurodegenerative phenotype (MGnD) [35] transition, [36]. Whether S1P activates TREM2 to facilitate microglia transition to these phenotypes, and then promote phagocytosis deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-phosphate, a Novel TREM2 Ligand, Promotes Phagocytosis and Reduce Ischemic Injury

Sun

Xue

et al. 2020

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Background: Activation of TREM2 protects against brain injury in ischemic stroke via immunoregulation. However, the endogenous ligand of TREM2 remains unknown. Here, we tested the hypothesis that S1P, an immunoregulator, functions as TREM2 ligand to promote microglial phagocytosis.Methods: SD rats, C57BL/6J mice and TREM2-/- mice were subjected to transient middle cerebral artery occlusion, and primary microglia were subjected to oxygen-glucose deprivation. Phagocytosis was investigated via immunofluorescence and two-photon microscope. LC-MS/MS, microscale thermophoresis and surface plasmon resonance were used to confirm the TREM2-S1P interaction.Results: FTY720, an analog of S1P, promoted microglial phagocytosis in ischemic stroke independent of S1PRs expressed on microglia. S1P was confirmed to be a novel endogenous ligand for TREM2 and promote cellular debris clearance. The enhanced cellular debris clearance ameliorated neurological score and infarct volume, relying on TREM2. Moreover, FTY720 was demonstrated to promote hemoglobin clearance in intracerebral hemorrhage and ameliorate hemorrhagic injury.Conlusions: The present work reveals for the first time that S1P acts as a novel endogenous ligand of TREM2 to effectively promote microglial phagocytosis, and provides a new lead compound for developing TREM2 modulator.

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TREM2 Regulates Microglial Cholesterol Metabolism Upon Chronic Phagocytic Challenge

Cited by 31 publications

References 0 publications

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes

Sphingosine 1-phosphate, a Novel TREM2 Ligand, Promotes Phagocytosis and Reduce Ischemic Injury

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