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

Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region.

EMBO Mol. Med. 12:e11227 (2020)
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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., alpha-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for alpha-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 beta-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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alzheimer's Disease ; Amyloid Beta-peptide ; Microglia ; Therapeutic Antibody ; Trem2; Amyloid Precursor Protein; Alzheimers-disease; Brain; Generation; Ectodomain; Presenilin; Responses; Cleavage; Survival; Mouse
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Journal EMBO Molecular Medicine
Quellenangaben Volume: 12, Issue: 4, Pages: , Article Number: e11227 Supplement: ,
Publisher Wiley
Publishing Place Chichester
Reviewing status Peer reviewed
Institute(s) CF Monoclonal Antibodies (CF-MAB)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502210-001
DOI 10.15252/emmm.201911227
WOS ID WOS:000526640800001
Scopus ID 85081240935
PubMed ID 32154671
Erfassungsdatum 2020-05-04
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