TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism
Abstract
Abstract 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.
Article Details
Authors (41)
Astrid F. Feiten
Kilian Dahm
Kai Schlepckow
Bettina van Lengerich
Jung H. Suh
Anika Reifschneider
Benedikt Wefers
Laura M. Bartos
Karin Wind-Mark
Lis de Weerd
Thomas Ulas
Elena De-Domenico
Pia Grundschöttel
Stefan Paulusch
Benjamin Tast
Tamisa Honda
Stephan A. Müller
Matthias Becker
Igor Khalin
Alessio Ricci
Arthur Liesz
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München
Bettina Brunner
Claudia Krenner
Katrin Buschmann
Brigitte Nuscher
Lena Spieth
Niklas Junker
Stefan A. Berghoff
Sonnet S. Davis
Jonas J. Neher
Biomedical Center, Biochemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München
Wolfgang Wurst
Nikolaus Plesnila
Joseph W. Lewcock
Mikael Simons
Stefan F. Lichtenthaler
Gilbert Di Paolo
Matthias Brendel
Anja Capell
Kathryn M. Monroe
Joachim L. Schultze
Christian Haass