Astrid Feiten, Kilian Dahm, Kai Schlepckow, Bettina van Lengerich, Jung H. Suh, Anika Reifschneider, Benedikt Wefers, Laura M. Bartos, Karin Wind, Lis de Weerd, T Ulas, Elena De Domenico, Pia Grundschöttel, Stefan Paulusch, Benjamin Tast, Tamisa Honda, Stefan A. Müller, Matthias Becker, Igor Khalin, Alessio Ricci, Arthur Liesz, Bettina Brunner, Claudia Krenner, Katrin Buschmann, Brigitte Nuscher, Lena Spieth, Niklas Junker, Stefan A. Berghoff, Sonnet S. Davis, Jonas J. Neher, Wolfgang Wurst, N. Plesnila, Joseph W. Lewcock, Mikael Simons, Stefan F. Lichtenthaler, Gilbert Di Paolo, Matthias Brendel, A. Capell, Kathryn M. Monroe, Joachim L. Schultze, Christian Haass
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.