[en] Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer's disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we demonstrate that genetic deletion of TREM2 or expression of a disease associated TREM2 variant in mice lead to differential accumulation of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits. Human brains with rare TREM2 AD risk variants also showed altered deposition of modified Aβ species in the different brain lesions as compared to cases with the common variant of TREM2. These findings indicate that TREM2 plays a critical role in the development and the composition of Aβ deposits, not only in extracellular plaques, but also intraneuronally, that both could contribute to the pathogenesis of AD.
Disciplines :
Neurology
Author, co-author :
Joshi, Pranav ; Department of Neurology, University of Bonn, Venusberg-Campus 1, (Formerly Sigmund-Freud-Str. 25), 53127, Bonn, Germany
Riffel, Florian ; Department of Neurology, University of Bonn, Venusberg-Campus 1, (Formerly Sigmund-Freud-Str. 25), 53127, Bonn, Germany
Kumar, Sathish ; Department of Neurology, University of Bonn, Venusberg-Campus 1, (Formerly Sigmund-Freud-Str. 25), 53127, Bonn, Germany
Villacampa, Nàdia ; Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital Bonn, Bonn, Germany ; Neuroinflammation Unit, German Center for Neurodegenerative Diseases e. V. (DZNE), Bonn, Germany
Theil, Sandra; Department of Neurology, University of Bonn, Venusberg-Campus 1, (Formerly Sigmund-Freud-Str. 25), 53127, Bonn, Germany
Parhizkar, Samira ; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
Haass, Christian; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Molecular Neurodegeneration Unit, German Center for Neurodegenerative Diseases e.V. (DZNE) Munich, Munich, Germany
Colonna, Marco; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA
HENEKA, Michael ; Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital Bonn, Bonn, Germany ; Neuroinflammation Unit, German Center for Neurodegenerative Diseases e. V. (DZNE), Bonn, Germany
Arzberger, Thomas; Molecular Neurodegeneration Unit, German Center for Neurodegenerative Diseases e.V. (DZNE) Munich, Munich, Germany ; Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany
Herms, Jochen; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Molecular Neurodegeneration Unit, German Center for Neurodegenerative Diseases e.V. (DZNE) Munich, Munich, Germany ; Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany
Walter, Jochen ; Department of Neurology, University of Bonn, Venusberg-Campus 1, (Formerly Sigmund-Freud-Str. 25), 53127, Bonn, Germany. jochen.walter@ukbonn.de
External co-authors :
yes
Language :
English
Title :
TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits.
Deutsche Forschungsgemeinschaft EU Innovative Medicines Initiative 2 Joint Undertaking
Funding text :
This work was supported by the Deutsche Forschungsgemeinschaft, Grant WA1477/6-6 (to JW), the EU Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU), Grant/Award Number: No 115976 (PHAGO). PJ thanks the BIGS neuroscience and the University of Bonn for their support. PJ also thanks Lorenz Haase, Research department fundamental physics, Max Planck Institute for Radio Astronomy, Bonn, for his critical suggestions on the analysis done in this study. Authors thank the Microscopy Core Facility of the Medical Faculty at the University of Bonn for providing support and instrumentation funded by the Deutsche Forschungsgemeinschaft, Project Number: 388169927.This work was supported by the Deutsche Forschungsgemeinschaft, Grant WA1477/6-6 (to JW), the EU Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU), Grant/Award Number: No 115976 (PHAGO). PJ thanks the BIGS neuroscience and the University of Bonn for their support. PJ also thanks Lorenz Haase, Research department fundamental physics, Max Planck Institute for Radio Astronomy, Bonn, for his critical suggestions on the analysis done in this study. Authors thank the Microscopy Core Facility of the Medical Faculty at the University of Bonn for providing support and instrumentation funded by the Deutsche Forschungsgemeinschaft, Project Number: 388169927.
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