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

Joshi, Pranav; Riffel, Florian; Kumar, Sathish; Villacampa, Nadia; Theil, Sandra; Parhizkar, Samira; Haass, Christian; Colonna, Marco; Heneka, Michael T.; Arzberger, Thomas; Herms, Jochen und Walter, Jochen (2021): TREM2 modulates differential deposition of modified and non-modified A beta species in extracellular plaques and intraneuronal deposits. In: Acta Neuropathologica Communications, Bd. 9, Nr. 1, 168

Abstract

Progressive accumulation of Amyloid-beta (A beta) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer's disease (AD). During disease progression, extracellular A beta plaques undergo specific changes in their composition by the sequential deposition of different modified A beta species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of A beta. 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 A beta 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 A beta species in extracellular plaques and intraneuronal deposits. Human brains with rare TREM2 AD risk variants also showed altered deposition of modified A beta 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 A beta deposits, not only in extracellular plaques, but also intraneuronally, that both could contribute to the pathogenesis of AD.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2051-5960
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198