Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Creators
- Kai Schlepckow
- Kathryn M Monroe
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Gernot Kleinberger
- Ludovico Cantuti-Castelvetri
- Samira Parhizkar
- Dan Xia
- Michael Willem
- Georg Werner
- Nadine Pettkus
- Bettina Brunner
- Alice Sülzen
- Brigitte Nuscher
- Heike Hampel
- Xianyuan Xiang
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Regina Feederle
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Sabina Tahirovic
- Joshua I Park
- Rachel Prorok
- Cathal Mahon
- Chun-Chi Liang
- Ju Shi
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Joseph W Lewcock
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Christian Haass
Description
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., a-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for a-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 b-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 diseaserelated 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.
Files
2020 Schlepckow - Enhancing protective microglial activities with a dual function tREM2 antibody to the stalk region.pdf
Files
(4.4 MB)
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