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@ARTICLE{Feiten:285462,
author = {Feiten, Astrid Feentje and Dahm, Kilian and Schlepckow, Kai
and van Lengerich, Bettina and Suh, Jung H and
Reifschneider, Anika and Wefers, Benedikt and Bartos, Laura
M and Wind, Karin and de Weerd, Lis and Ulas, Thomas and
De-Domenico, Elena and Grundschöttel, Pia and Paulusch,
Stefan and Tast, Benjamin and Honda, Tamisa and Müller,
Stephan A and Becker, Matthias and Khalin, Igor and Ricci,
Alessio and Liesz, Arthur and Brunner, Bettina and Krenner,
Claudia and Buschmann, Katrin and Nuscher, Brigitte and
Spieth, Lena and Junker, Niklas and Berghoff, Stefan A and
Davis, Sonnet S and Neher, Jonas J and Wurst, Wolfgang and
Plesnila, Nikolaus and Lewcock, Joseph W and Simons, Mikael
and Lichtenthaler, Stefan F and Di Paolo, Gilbert and
Brendel, Matthias and Capell, Anja and Monroe, Kathryn M and
Schultze, Joachim L and Haass, Christian},
title = {{TREM}2 expression level is critical for microglial state,
metabolic capacity and efficacy of {TREM}2 agonism.},
journal = {Nature Communications},
volume = {17},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2026-00240},
pages = {2002},
year = {2026},
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.},
cin = {AG Haass / AG Schultze / AG Lichtenthaler / AG Becker / AG
Neher (München) / AG Simons / AG Wurst / PRECISE},
ddc = {500},
cid = {I:(DE-2719)1110007 / I:(DE-2719)1013038 /
I:(DE-2719)1110006 / I:(DE-2719)5000079 / I:(DE-2719)1110011
/ I:(DE-2719)1110008 / I:(DE-2719)1140001 /
I:(DE-2719)1013031},
pnm = {352 - Disease Mechanisms (POF4-352) / 354 - Disease
Prevention and Healthy Aging (POF4-354) / 351 - Brain
Function (POF4-351)},
pid = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-354 /
G:(DE-HGF)POF4-351},
experiment = {EXP:(DE-2719)PRECISE-20190321},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41580393},
pmc = {pmc:PMC12936096},
doi = {10.1038/s41467-026-68706-8},
url = {https://pub.dzne.de/record/285462},
}