Journal Article

DZNE-2020-01072

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

Schlepckow, K. (First author)DZNE* ; Monroe, K. M. ; Kleinberger, G. ; Cantuti-Castelvetri, L.DZNE* ; Parhizkar, S. ; Xia, D. ; Willem, M. ; Werner, G. ; Pettkus, N. ; Brunner, B.DZNE* ; Sülzen, A.DZNE* ; Nuscher, B. ; Hampel, H. ; Xiang, X. ; Feederle, R.DZNE* ; Tahirovic, S.DZNE* ; Park, J. I. ; Prorok, R. ; Mahon, C. ; Liang, C. ; Shi, J. ; Kim, D. J. ; Sabelström, H. ; Huang, F. ; Di Paolo, G. ; Simons, M.DZNE* ; Lewcock, J. W. ; Haass, C. (Last author)DZNE*

2020
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.15252/emmm.201911227

Abstract: 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.

Keyword(s): Amyloid beta-Peptides (MeSH) ; Animals (MeSH) ; Antibodies, Monoclonal: pharmacology (MeSH) ; Cell Line, Tumor (MeSH) ; Female (MeSH) ; Macrophages (MeSH) ; Membrane Glycoproteins: immunology (MeSH) ; Mice (MeSH) ; Microglia: pathology (MeSH) ; Multiple Myeloma (MeSH) ; Rats (MeSH) ; Rats, Wistar (MeSH) ; Receptors, Immunologic: immunology (MeSH)

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)
2. Core KAP (Kooperationseinheit Angewandte Präventionsforschung) (Core Technical Staff)
3. Juvenile Neurodegeneration (AG Tahirovic)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Web of Science Core Collection

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