TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism

Nat Commun. 2026 Jan 24;17(1):2002. doi: 10.1038/s41467-026-68706-8.

Astrid F Feiten ^# ¹ ², Kilian Dahm ^# ³ ⁴ ⁵, Kai Schlepckow ^# ², Bettina van Lengerich ⁶, Jung H Suh ⁶, Anika Reifschneider ¹, Benedikt Wefers ², Laura M Bartos ⁷, Karin Wind-Mark ⁷, Lis de Weerd ², Thomas Ulas ³ ⁵ ⁸, Elena De-Domenico ³ ⁵ ⁸, Pia Grundschöttel ³ ⁵ ⁸, Stefan Paulusch ³ ⁵ ⁸, Benjamin Tast ⁹, Tamisa Honda ⁹, Stephan A Müller ² ¹⁰, Matthias Becker ³ ¹¹, Igor Khalin ¹² ¹³, Alessio Ricci ¹², Arthur Liesz ¹² ¹⁴, Bettina Brunner ², Claudia Krenner ¹, Katrin Buschmann ¹, Brigitte Nuscher ¹, Lena Spieth ² ¹⁵, Niklas Junker ² ¹⁵, Stefan A Berghoff ² ¹⁵, Sonnet S Davis ⁶, Jonas J Neher ¹ ² ¹⁴, Wolfgang Wurst ² ¹⁶ ¹⁷, Nikolaus Plesnila ¹² ¹⁴, Joseph W Lewcock ⁶, Mikael Simons ² ¹² ¹⁴ ¹⁵, Stefan F Lichtenthaler ² ¹⁰ ¹⁴, Gilbert Di Paolo ⁶, Matthias Brendel ² ⁷ ¹⁴, Anja Capell ¹ ², Kathryn M Monroe ¹⁸, Joachim L Schultze ¹⁹ ²⁰ ²¹, Christian Haass ²² ²³ ²⁴

Affiliations

1 Metabolic Biochemistry, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians Universität München, Munich, Germany.
2 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
3 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
4 Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany.
5 Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
6 Denali Therapeutics, Inc., South San Francisco, California, 94080, USA.
7 Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians Universität München, Munich, Germany.
8 Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Western German Genome Center (WGGC), Bonn, Germany.
9 Biomedical Center, Faculty of Medicine, Core Facility Flow Cytometry, Ludwig-Maximilians Universität München, Munich, Germany.
10 Neuroproteomics, School of Medicine and Health, TUM University Hospital, Technical University of Munich (TUM), Munich, Germany.
11 Modular High-Performance Computing and Artificial Intelligence, Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
12 Institute for Stroke and Dementia Research,, University Hospital, Ludwig-Maximilians Universität München, Munich, Germany.
13 Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France.
14 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
15 Institute of Neuronal Cell Biology, Technical University Munich (TUM), Munich, Germany.
16 Institute of Developmental Genetics, Helmholtz Zentrum, Munich, Germany.
17 Technical University Munich (TUM), TUM Senior Excellence Faculty (SEF), Munich, Germany.
18 Denali Therapeutics, Inc., South San Francisco, California, 94080, USA. [email protected].
19 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. [email protected].
20 Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany. [email protected].
21 Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Western German Genome Center (WGGC), Bonn, Germany. [email protected].
22 Metabolic Biochemistry, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians Universität München, Munich, Germany. [email protected].
23 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. [email protected].
24 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. [email protected].
# Contributed equally.

PMID: 41580393 DOI: 10.1038/s41467-026-68706-8

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.

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