A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in Alzheimer’s disease (AD) by regulating microglia migration toward, and phagocytosis of oligomeric amyloid-β (oAβ) and amyloid plaques. Studies in rodent models of AD have shown that mice with increased TREM2 expression have reduced amyloid pathology. Here, we identified a TREM2 agonist monoclonal Ab (Ab18) by panning a phage-displayed single-chain variable fragment Ab library. By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold. Stronger TREM2 activation led to enhanced microglia phagocytosis of the oAβ-lipid complex, migration toward oAβ, and improved microglia survival in vitro. Mechanistic studies showed increased TREM2 clustering on microglia by the tetravalent Ab18 TVD-Ig without altering microglial TREM2 amount. An engineered bispecific Ab targeting TREM2 and transferrin receptor (TfR; Ab18 TVD-Ig/αTfR) improved Ab brain entry by more than 10-fold with a broad brain parenchyma distribution. Weekly treatment of 5XFAD mice (a model of AD) with Ab18 TVD-Ig/αTfR showed a considerable reduction of amyloid burden with increased microglia migration to and phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, reduced endogenous tau hyperphosphorylation, and decreased phosphorylated neurofilament H immunostaining. This study demonstrated the feasibility of engineering multivalent TREM2 agonistic Ab coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo. This Ab engineering approach enables the development of effective TREM2-targeting therapies for AD.
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The current consensus is that the microglial response to plaques confers protection.
“The current consensus is that the microglial response to plaques confers protection.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [100]
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- Authors
- Zhao, P., Xu, Y., Jiang, L., Fan, X., Li, L., Li, X., Arase, H., Zhao, Y., Cao, W., Zheng, H., Xu, H., Tong, Q., Zhang, N., & An, Z.
- Affiliations
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Xiamen University (CN)
- The University of Texas Health Science Center at Houston (US)
- Baylor College of Medicine (US)
- Corresponding author
- Zhang, Ningyan
- An, Zhiqiang
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2022-09-07
- Volume
- 14
- Issue
- 661
- Pages
- eabq0095-eabq0095
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W4294884802
- Cited by
- 141
- References
- 28
- Citations by year
- 2026: 32 · 2025: 52 · 2024: 31 · 2023: 20 · 2022: 6
- FWCI
- 16.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (18H05279, 22H04989)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, amyloid-beta, microglia, tetravalent antibody, transferrin receptor, bispecific antibodies, microglial phagocytosis, microglial migration, amyloid plaques, 5xFAD mice, tau hyperphosphorylation, neuroinflammation, phage display
- MeSH terms
- Alzheimer Disease, Amyloid, Amyloidosis, Animals, Antibodies, Disease Models, Animal, Membrane Glycoproteins, Receptors, Immunologic, Amyloid beta-Peptides, Mice, Plaque, Amyloid
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