TY  - JOUR
AU  - Joshi, Pranav
AU  - Riffel, Florian
AU  - Satoh, Kanayo
AU  - Enomoto, Masahiro
AU  - Qamar, Seema
AU  - Scheiblich, Hannah
AU  - Villacampa, Nàdia
AU  - Kumar, Sathish
AU  - Theil, Sandra
AU  - Parhizkar, Samira
AU  - Haass, Christian
AU  - Heneka, Michael
AU  - Fraser, Paul E
AU  - St George-Hyslop, Peter
AU  - Walter, Jochen
TI  - Differential interaction with TREM2 modulates microglial uptake of modified Aβ species.
JO  - Glia
VL  - 69
IS  - 12
SN  - 1098-1136
CY  - Bognor Regis [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2021-01357
SP  - 2917 - 2932
PY  - 2021
AB  - 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.
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Disease Models, Animal
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Mice
KW  - Mice, Transgenic
KW  - Microglia: metabolism
KW  - Receptors, Immunologic: genetics
KW  - Receptors, Immunologic: metabolism
KW  - Alzheimer's disease (Other)
KW  - FTD mutation (Other)
KW  - TREM2 (Other)
KW  - amyloid β (Other)
KW  - phosphorylation (Other)
KW  - post-translational modification (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34427354
DO  - DOI:10.1002/glia.24077
UR  - https://pub.dzne.de/record/162700
ER  -