Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease
| Autor: | Dawn Weishuhn, Simone Brioschi, Diana Cha, Marco Colonna, Daniel Yoo, Sara Rao, Samuel A. Hasson, Jodi Bradley, Peng Luan, Ian Foltz, Shilpa Sambashivan, Shoutang Wang, Daniel C. Ellwanger, Menno Van Lookeren Campagne, Susan Gilfillan, Palaniswami Rathanaswami, Ryan Case, Lydia Green, Zhifei Shao |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Genetically modified mouse Chemokine Amyloid beta Mice Transgenic Mice Myelin Sex Factors Alzheimer Disease medicine Animals Humans Receptors Immunologic Receptor Cell Proliferation Amyloid beta-Peptides Membrane Glycoproteins Multidisciplinary Microglia biology TREM2 Chemistry Antibodies Monoclonal Brain Biological Sciences Ligand (biochemistry) Antibodies Neutralizing Cell biology Disease Models Animal Kinetics HEK293 Cells medicine.anatomical_structure Gene Expression Regulation Mutation biology.protein Female Chemokines Protein Binding |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s disease (AD) risk is associated with the TREM2(R47H) variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2(CV)) or TREM2(R47H). scRNA-seq of microglia from TREM2(CV)-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2(R47H)-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2(CV)-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2(R47H)-5XFAD mice. In TREM2(CV)-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2(R47H)-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation. |
| Databáze: | OpenAIRE |
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