ORCID: https://orcid.org/0000-0002-9134-2852; Dahm, Kilian ORCID: https://orcid.org/0000-0002-6819-2622; Schlepckow, Kai ORCID: https://orcid.org/0000-0002-1119-2293; Lengerich, Bettina van; Suh, Jung H. ORCID: https://orcid.org/0000-0001-8119-326X; Reifschneider, Anika; Wefers, Benedikt ORCID: https://orcid.org/0000-0002-2492-9389; Bartos, Laura M. ORCID: https://orcid.org/0009-0007-6158-319X; Wind-Mark, Karin ORCID: https://orcid.org/0000-0002-5461-1873; Weerd, Lis de ORCID: https://orcid.org/0000-0002-3641-1851; Ulas, Thomas; De-Domenico, Elena ORCID: https://orcid.org/0000-0003-0336-8284; Grundschöttel, Pia; Paulusch, Stefan; Tast, Benjamin; Honda, Tamisa ORCID: https://orcid.org/0000-0001-5654-1162; Müller, Stephan A. ORCID: https://orcid.org/0000-0003-3414-307X; Becker, Matthias ORCID: https://orcid.org/0000-0002-7120-4508; Khalin, Igor ORCID: https://orcid.org/0000-0003-1041-5747; Ricci, Alessio ORCID: https://orcid.org/0000-0002-3051-8113; Liesz, Arthur ORCID: https://orcid.org/0000-0002-9069-2594; Brunner, Bettina; Krenner, Claudia; Buschmann, Katrin; Nuscher, Brigitte ORCID: https://orcid.org/0009-0000-4661-0742; Spieth, Lena; Junker, Niklas; Berghoff, Stefan A.; Davis, Sonnet S. ORCID: https://orcid.org/0000-0001-7189-1427; Neher, Jonas J. ORCID: https://orcid.org/0000-0003-1346-8924; Wurst, Wolfgang ORCID: https://orcid.org/0000-0003-4422-7410; Plesnila, Nikolaus ORCID: https://orcid.org/0000-0001-8832-228X; Lewcock, Joseph W. ORCID: https://orcid.org/0000-0003-3012-7881; Simons, Mikael ORCID: https://orcid.org/0000-0001-5329-192X; Lichtenthaler, Stefan F. ORCID: https://orcid.org/0000-0003-2211-2575; Paolo, Gilbert Di ORCID: https://orcid.org/0000-0003-1032-1265; Brendel, Matthias ORCID: https://orcid.org/0000-0002-9247-2843; Capell, Anja ORCID: https://orcid.org/0000-0003-3118-911X; Monroe, Kathryn M. ORCID: https://orcid.org/0000-0002-6901-1176; Schultze, Joachim L. ORCID: https://orcid.org/0000-0003-2812-9853 und Haass, Christian ORCID: https://orcid.org/0000-0002-4869-1627
(2026):
TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.
In: Nature Communications [Forthcoming]
[PDF, 7MB]
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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine > Biomedical Center Medicine > Munich Cluster for Systems Neurology (SyNergy) Medicine > Institute for Stroke and Dementia Research (ISD) Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Nuclear Medicine |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-132196-1 |
| ISSN: | 2041-1723 |
| Language: | English |
| Item ID: | 132196 |
| Date Deposited: | 16. Feb 2026 13:58 |
| Last Modified: | 16. Feb 2026 13:58 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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