Language
English
Publication Date
4-3-2024
Journal
Science Translational Medicine
DOI
10.1126/scitranslmed.adj9052
PMID
38569016
PMCID
PMC11977387
PubMedCentral® Posted Date
4-8-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
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 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.
Keywords
Humans, Mice, Animals, Microglia, Antibodies, Receptors, Cell Surface, Amyloid, Disease Models, Animal, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Leukocytes, Mice, Transgenic, Membrane Glycoproteins, Receptors, Immunologic
Published Open-Access
yes
Recommended Citation
Hou, Jinchao; Chen, Yun; Cai, Zhangying; et al., "Antibody-Mediated Targeting of Human Microglial Leukocyte Ig-Like Receptor B4 Attenuates Amyloid Pathology in a Mouse Model" (2024). The Brown Foundation: Institute of Molecular Medicine. 41.
https://digitalcommons.library.tmc.edu/molecular_med/41