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      Loss of TREM2 function increases amyloid seeding but reduces plaque associated ApoE

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 1 , 2 , 6 , 6 , 1 , 7 , 8 , 9 , 10 , 11 , 2 , 3 , 12 , 13 , 3 , 12 , 3 , 3 , 3 , 2 , 3 , 4 , 1 , 1 , 10 , 14 , 2 , 6 , 2 , 3 , 2 , 6 , 8 , 15 , 15 , 16 , 7 , 9 , * , 1 , 2 , 3 , *
      Nature neuroscience
      Alzheimer’s disease, amyloid plaque seeding, ApoE, microglia, neurodegeneration, TREM2

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          Abstract

          Coding variants in the triggering receptor expressed on myeloid cells 2 ( TREM2) are associated with late onset Alzheimer’s disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque associated Apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss of function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2 early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque associated ApoE.

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          Most cited references30

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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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            Microglial signatures and their role in health and disease

            Microglia are the primary innate immune cells in the CNS. In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages. In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment.
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              The evolution of preclinical Alzheimer's disease: implications for prevention trials.

              As the field begins to test the concept of a "preclinical" stage of neurodegenerative disease, when the pathophysiological process has begun in the brain, but clinical symptoms are not yet manifest, a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer's disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic at-risk and amyloid at-risk cohorts, with several more trials in the planning stages, and should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression. This review will highlight recent progress in cognitive, imaging, and biomarker outcomes in the field of preclinical AD, and the remaining gaps in knowledge.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                29 November 2018
                07 January 2019
                February 2019
                07 July 2019
                : 22
                : 2
                : 191-204
                Affiliations
                [1 ]Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
                [2 ]Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
                [3 ]German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
                [4 ]Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany
                [5 ]Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany
                [6 ]Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität München; Munich, Germany
                [7 ]Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
                [8 ]Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany
                [9 ]Department of Neurology, Medical Center University of Freiburg; Faculty of Medicine University of Freiburg, Freiburg, Germany
                [10 ]Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA, USA
                [11 ]Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [12 ]Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
                [13 ]Institute for Advanced Study, Technische Universität München, Garching, Germany.
                [14 ]Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                [15 ]Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
                [16 ]German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany
                Author notes
                [#]

                Current address: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland

                Author contributions

                C.H., M.M.L., G.K. and S.P. conceived the study and analyzed the results. C.H. wrote the manuscript with help from M.M.L., S.P., T.A., G.K., M.B. and D.M.H. and further input from all co-authors. S.P. and N.K. performed seeding experiments; S.P. and M.X. performed the ApoE stainings. M.B., M.D., C.F., P.B., and A.R. performed PET imaging and quantitative PET analyses. G.E. made GE-180 cassettes available through an early access model. A.E., A.G. and S.P. performed the three dimensional image analyses. O.B. and S.K. provided independent immunohistochemical data and interpretation on ApoE. D.M.H. interpreted the ApoE stainings and provided appropriate ApoE antibodies. T.A. provided human brain sections and interpreted the immunohistochemical analyses. G.K. and N.P. performed TREM2 sequencing and D.E. PSEN1, PSEN2 and APP sequencing of human autopsy cases. S.T., A.C., L.S.M., S.A.M. and S.F.L. prepared primary microglial lysates and measured ApoE levels by mass spectrometry. M.W. provided technical advice for protein extraction and ApoE experiments. D.E. genotyped AD cases. S.A.G. and J.J.N. provided brain sections from microglia depleted mice.

                Article
                NIHMS1512778
                10.1038/s41593-018-0296-9
                6417433
                30617257
                7082673d-0981-4593-9170-6421de8b9279

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                Article

                Neurosciences
                alzheimer’s disease,amyloid plaque seeding,apoe,microglia,neurodegeneration,trem2
                Neurosciences
                alzheimer’s disease, amyloid plaque seeding, apoe, microglia, neurodegeneration, trem2

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