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Hou, Jinchao; Chen, Yun; Cai, Zhangying; Heo, Gyu Seong; Yuede, Carla M.; Wang, Zuoxu; Lin, Kent; Saadi, Fareeha; Trsan, Tihana; Nguyen, Aivi T.; Constantopoulos, Eleni; Larsen, Rachel A.; Zhu, Yiyang; Wagner, Nicole D.; McLaughlin, Nolan; Kuang, Xinyi Cynthia; Barrow, Alexander D.; Li, Dian; Zhou, Yingyue; Wang, Shoutang; Gilfillan, Susan; Gross, Michael L.; Brioschi, Simone; Liu, Yongjian; [...]

Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model

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  • Medientyp: E-Artikel
  • Titel: Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model
  • Beteiligte: Hou, Jinchao; Chen, Yun; Cai, Zhangying; Heo, Gyu Seong; Yuede, Carla M.; Wang, Zuoxu; Lin, Kent; Saadi, Fareeha; Trsan, Tihana; Nguyen, Aivi T.; Constantopoulos, Eleni; Larsen, Rachel A.; Zhu, Yiyang; Wagner, Nicole D.; McLaughlin, Nolan; Kuang, Xinyi Cynthia; Barrow, Alexander D.; Li, Dian; Zhou, Yingyue; Wang, Shoutang; Gilfillan, Susan; Gross, Michael L.; Brioschi, Simone; Liu, Yongjian; [...]
  • Erschienen: American Association for the Advancement of Science (AAAS), 2024
  • Erschienen in: Science Translational Medicine, 16 (2024) 741
  • Sprache: Englisch
  • DOI: 10.1126/scitranslmed.adj9052
  • ISSN: 1946-6234; 1946-6242
  • Entstehung:
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  • Beschreibung: Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4 , we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.