TY - JOUR
T1 - Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model
AU - Hou, Jinchao
AU - Chen, Yun
AU - Cai, Zhangying
AU - Heo, Gyu Seong
AU - Yuede, Carla M.
AU - Wang, Zuoxu
AU - Lin, Kent
AU - Saadi, Fareeha
AU - Trsan, Tihana
AU - Nguyen, Aivi T.
AU - Constantopoulos, Eleni
AU - Larsen, Rachel A.
AU - Zhu, Yiyang
AU - Wagner, Nicole D.
AU - McLaughlin, Nolan
AU - Kuang, Xinyi Cynthia
AU - Barrow, Alexander D.
AU - Li, Dian
AU - Zhou, Yingyue
AU - Wang, Shoutang
AU - Gilfillan, Susan
AU - Gross, Michael L.
AU - Brioschi, Simone
AU - Liu, Yongjian
AU - Holtzman, David M.
AU - Colonna, Marco
N1 - Publisher Copyright:
copyright © 2024 The Authors, some rights reserved.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85190076531&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adj9052
DO - 10.1126/scitranslmed.adj9052
M3 - Article
C2 - 38569016
AN - SCOPUS:85190076531
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 741
M1 - eadj9052
ER -