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Nat Neurosci. 2019 Feb;22(2):191-204. doi: 10.1038/s41593-018-0296-9. Epub 2019 Jan 7.

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

Author information

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, and 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 Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
16
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
17
German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany.
18
Department of Neurology, Medical Center University of Freiburg, and Faculty of Medicine, University of Freiburg, Freiburg, Germany. melanie.meyer-luehmann@uniklinik-freiburg.de.
19
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
20
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
21
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.

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.

PMID:
30617257
PMCID:
PMC6417433
DOI:
10.1038/s41593-018-0296-9
[Indexed for MEDLINE]
Free PMC Article

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