TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

Acta Neuropathologica Communications

Samira Parhizkar¹  Christian Haass²  Nàdia Villacampa³  Michael T. Heneka³  Pranav Joshi⁴  Jochen Walter⁴  Sandra Theil⁴  Sathish Kumar⁴  Florian Riffel⁴  Marco Colonna⁵  Thomas Arzberger⁶  Jochen Herms⁷ 

[1] Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany;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;Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital Bonn, Bonn, Germany;Neuroinflammation Unit, German Center for Neurodegenerative Diseases e. V. (DZNE), Bonn, Germany;Department of Neurology, University of Bonn, Venusberg-Campus 1, (Formerly Sigmund-Freud-Str. 25), 53127, Bonn, Germany;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA;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;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;

关键词: TREM2;    Microglia;    Post-translational modification;    Aβ;    Intraneuronal;    Vascular deposits;   

DOI  :  10.1186/s40478-021-01263-x

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY