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