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      Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

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          Abstract

          The R47H variant of the microglia gene TREM2 has been linked to a significantly higher risk of Alzheimer’s disease. In this study, Song et al. generate human TREM2-expressing mice and demonstrate that R47H leads to a decreased microglia number and activation as well as a decreased presence of soluble TREM2 on neurons and plaques in a mouse model of Alzheimer’s disease.

          Abstract

          Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction.

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          Most cited references24

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          TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.

          Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. β-amyloid (Aβ) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Aβ-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT.
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            Cutting edge: TREM-2 attenuates macrophage activation.

            The triggering receptor expressed on myeloid cells 2 (TREM-2) delivers intracellular signals through the adaptor DAP12 to regulate myeloid cell function both within and outside the immune system. The role of TREM-2 in immunity has been obscured by the failure to detect expression of the TREM-2 protein in vivo. In this study, we show that TREM-2 is expressed on macrophages infiltrating the tissues from the circulation and that alternative activation with IL-4 can induce TREM-2. TREM-2 expression is abrogated by macrophage maturation with LPS of IFN-gamma. Using TREM-2(-/-) mice, we find that TREM-2 functions to inhibit cytokine production by macrophages in response to the TLR ligands LPS, zymosan, and CpG. Furthermore, we find that TREM-2 completely accounts for the increased cytokine production previously reported by DAP12(-/-) macrophages. Taken together, these data show that TREM-2 is expressed on newly differentiated and alternatively activated macrophages and functions to restrain macrophage activation.
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              Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2).

              Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons. Here, we report apolipoprotein E (apoE) as a novel ligand for TREM2. Using a biochemical assay, we demonstrated high-affinity binding of apoE to human TREM2. The functional significance of this binding was highlighted by increased phagocytosis of apoE-bound apoptotic N2a cells by primary microglia in a manner that depends on TREM2 expression. Moreover, when the AD-associated TREM2-R47H mutant was used in biochemical assays, apoE binding was vastly reduced. Our data demonstrate that apoE-TREM2 interaction in microglia plays critical roles in modulating phagocytosis of apoE-bound apoptotic neurons and establish a critical link between two proteins whose genes are strongly linked to the risk for AD.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                05 March 2018
                : 215
                : 3
                : 745-760
                Affiliations
                [1 ]Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO
                [2 ]Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
                Author notes
                Correspondence to Marco Colonna: mcolonna@ 123456wustl.edu
                [*]

                W.M. Song and S. Joshita contributed equally to this paper.

                Author information
                http://orcid.org/0000-0002-6608-4628
                http://orcid.org/0000-0002-6364-9654
                http://orcid.org/0000-0002-6507-4989
                http://orcid.org/0000-0003-1672-0996
                http://orcid.org/0000-0001-5222-4987
                Article
                20171529
                10.1084/jem.20171529
                5839761
                29321225
                e6d68294-03d4-469e-ac1d-5a78f95e7d40
                © 2018 Song et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 21 August 2017
                : 07 November 2017
                : 18 December 2017
                Funding
                Funded by: National Cancer Institute, DOI https://doi.org/10.13039/100000054;
                Award ID: P30 CA91842
                Funded by: Institute of Clinical and Translational Sciences, DOI https://doi.org/10.13039/100007930;
                Funded by: Clinical and Translational Science Awards
                Funded by: National Center for Research Resources, DOI https://doi.org/10.13039/100000097;
                Award ID: UL1TR000448
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Funded by: Washington University School of Medicine in St. Louis, DOI https://doi.org/10.13039/100011912;
                Funded by: Children’s Discovery Institute of Washington University
                Funded by: St. Louis Children’s Hospital
                Award ID: CDI-CORE-2015-505
                Funded by: National Institute for Neurological Disorders and Stroke, DOI https://doi.org/10.13039/100000065;
                Award ID: NS086741
                Funded by: NIH, DOI https://doi.org/10.13039/100000002;
                Award ID: 5T32CA009547-30
                Award ID: P30DK052574
                Award ID: P30DK020579
                Award ID: RF1 AG05148501
                Funded by: Cure Alzheimer’s Fund, DOI https://doi.org/10.13039/100007625;
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