TY  - JOUR
AU  - Feiten, Astrid Feentje
AU  - Dahm, Kilian
AU  - Schlepckow, Kai
AU  - van Lengerich, Bettina
AU  - Suh, Jung H
AU  - Reifschneider, Anika
AU  - Wefers, Benedikt
AU  - Bartos, Laura M
AU  - Wind, Karin
AU  - de Weerd, Lis
AU  - Ulas, Thomas
AU  - De-Domenico, Elena
AU  - Grundschöttel, Pia
AU  - Paulusch, Stefan
AU  - Tast, Benjamin
AU  - Honda, Tamisa
AU  - Müller, Stephan A
AU  - Becker, Matthias
AU  - Khalin, Igor
AU  - Ricci, Alessio
AU  - Liesz, Arthur
AU  - Brunner, Bettina
AU  - Krenner, Claudia
AU  - Buschmann, Katrin
AU  - Nuscher, Brigitte
AU  - Spieth, Lena
AU  - Junker, Niklas
AU  - Berghoff, Stefan A
AU  - Davis, Sonnet S
AU  - Neher, Jonas J
AU  - Wurst, Wolfgang
AU  - Plesnila, Nikolaus
AU  - Lewcock, Joseph W
AU  - Simons, Mikael
AU  - Lichtenthaler, Stefan F
AU  - Di Paolo, Gilbert
AU  - Brendel, Matthias
AU  - Capell, Anja
AU  - Monroe, Kathryn M
AU  - Schultze, Joachim L
AU  - Haass, Christian
TI  - TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.
JO  - Nature Communications
VL  - 17
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00240
SP  - 2002
PY  - 2026
AB  - Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.
LB  - PUB:(DE-HGF)16
C6  - pmid:41580393
C2  - pmc:PMC12936096
DO  - DOI:10.1038/s41467-026-68706-8
UR  - https://pub.dzne.de/record/285462
ER  -