TY  - JOUR
AU  - Schlepckow, Kai
AU  - Monroe, Kathryn M
AU  - Kleinberger, Gernot
AU  - Cantuti-Castelvetri, Ludovico
AU  - Parhizkar, Samira
AU  - Xia, Dan
AU  - Willem, Michael
AU  - Werner, Georg
AU  - Pettkus, Nadine
AU  - Brunner, Bettina
AU  - Sülzen, Alice
AU  - Nuscher, Brigitte
AU  - Hampel, Heike
AU  - Xiang, Xianyuan
AU  - Feederle, Regina
AU  - Tahirovic, Sabina
AU  - Park, Joshua I
AU  - Prorok, Rachel
AU  - Mahon, Cathal
AU  - Liang, Chun‐Chi
AU  - Shi, Ju
AU  - Kim, Do Jin
AU  - Sabelström, Hanna
AU  - Huang, Fen
AU  - Di Paolo, Gilbert
AU  - Simons, Mikael
AU  - Lewcock, Joseph W
AU  - Haass, Christian
TI  - Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region
JO  - EMBO molecular medicine
VL  - 12
IS  - 4
SN  - 1757-4676
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2020-01072
SP  - e11227
PY  - 2020
AB  - Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state.
KW  - Amyloid beta-Peptides
KW  - Animals
KW  - Antibodies, Monoclonal: pharmacology
KW  - Cell Line, Tumor
KW  - Female
KW  - Macrophages
KW  - Membrane Glycoproteins: immunology
KW  - Mice
KW  - Microglia: pathology
KW  - Multiple Myeloma
KW  - Rats
KW  - Rats, Wistar
KW  - Receptors, Immunologic: immunology
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7136959
C6  - pmid:32154671
DO  - DOI:10.15252/emmm.201911227
UR  - https://pub.dzne.de/record/151484
ER  -