Journal Article

DZNE-2026-00240

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.

Feiten, A. F. (First author)DZNE* ; Dahm, K. (First author)DZNE* ; Schlepckow, K. (First author)DZNE* ; van Lengerich, B. ; Suh, J. H. ; Reifschneider, A. ; Wefers, B.DZNE* ; Bartos, L. M. ; Wind, K.Extern* ; de Weerd, L.DZNE* ; Ulas, T.DZNE* ; De-Domenico, E.DZNE* ; Grundschöttel, P.DZNE* ; Paulusch, S.DZNE* ; Tast, B. ; Honda, T. ; Müller, S. A.DZNE* ; Becker, M.DZNE* ; Khalin, I. ; Ricci, A. ; Liesz, A. ; Brunner, B.DZNE* ; Krenner, C.Extern* ; Buschmann, K.Extern* ; Nuscher, B. ; Spieth, L.DZNE* ; Junker, N.DZNE* ; Berghoff, S. A.DZNE* ; Davis, S. S. ; Neher, J. J.DZNE* ; Wurst, W.DZNE* ; Plesnila, N. ; Lewcock, J. W. ; Simons, M.DZNE* ; Lichtenthaler, S. F.DZNE* ; Di Paolo, G. ; Brendel, M.DZNE* ; Capell, A.DZNE* ; Monroe, K. M. ; Schultze, J. L.DZNE* ; Haass, C. (Last author)DZNE*

2026
Springer Nature [London]

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Please use a persistent id in citations: 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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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Neuroproteomics (AG Lichtenthaler)
4. Modular High Performance Computing and Artificial Intelligence (AG Becker)
5. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))
6. Molecular Neurobiology (AG Simons)
7. Genome Engineering (AG Wurst)
8. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

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