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@ARTICLE{Joshi:162700,
author = {Joshi, Pranav and Riffel, Florian and Satoh, Kanayo and
Enomoto, Masahiro and Qamar, Seema and Scheiblich, Hannah
and Villacampa, Nàdia and Kumar, Sathish and Theil, Sandra
and Parhizkar, Samira and Haass, Christian and Heneka,
Michael and Fraser, Paul E and St George-Hyslop, Peter and
Walter, Jochen},
title = {{D}ifferential interaction with {TREM}2 modulates
microglial uptake of modified {A}β species.},
journal = {Glia},
volume = {69},
number = {12},
issn = {1098-1136},
address = {Bognor Regis [u.a.]},
publisher = {Wiley-Liss},
reportid = {DZNE-2021-01357},
pages = {2917 - 2932},
year = {2021},
abstract = {Rare coding variants of the microglial triggering receptor
expressed on myeloid cells 2 (TREM2) confer an increased
risk for Alzheimer's disease (AD) characterized by the
progressive accumulation of aggregated forms of amyloid β
peptides (Aβ). Aβ peptides are generated by proteolytic
processing of the amyloid precursor protein (APP).
Heterogeneity in proteolytic cleavages and additional
post-translational modifications result in the production of
several distinct Aβ variants that could differ in their
aggregation behavior and toxic properties. Here, we sought
to assess whether post-translational modifications of Aβ
affect the interaction with TREM2. Biophysical and
biochemical methods revealed that TREM2 preferentially
interacts with oligomeric Aβ, and that phosphorylation of
Aβ increases this interaction. Phosphorylation of Aβ also
affected the TREM2 dependent interaction and phagocytosis by
primary microglia and in APP transgenic mouse models. Thus,
TREM2 function is important for sensing phosphorylated Aβ
variants in distinct aggregation states and reduces the
accumulation and deposition of these toxic Aβ species in
preclinical models of Alzheimer's disease.},
keywords = {Alzheimer Disease: genetics / Alzheimer Disease: metabolism
/ Amyloid beta-Peptides: metabolism / Amyloid beta-Protein
Precursor: genetics / Amyloid beta-Protein Precursor:
metabolism / Animals / Disease Models, Animal / Membrane
Glycoproteins: genetics / Membrane Glycoproteins: metabolism
/ Mice / Mice, Transgenic / Microglia: metabolism /
Receptors, Immunologic: genetics / Receptors, Immunologic:
metabolism / Alzheimer's disease (Other) / FTD mutation
(Other) / TREM2 (Other) / amyloid β (Other) /
phosphorylation (Other) / post-translational modification
(Other)},
cin = {Biomarker / AG Heneka / AG Haass / Tech Transfer},
ddc = {610},
cid = {I:(DE-2719)1011301 / I:(DE-2719)1011303 /
I:(DE-2719)1110007 / I:(DE-2719)1030028},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352) / 899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352 /
G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34427354},
doi = {10.1002/glia.24077},
url = {https://pub.dzne.de/record/162700},
}