Antibody-mediated targeting of human microglial LILRB4 attenuates amyloid-dependent pathology

Microglia help limit the progression of Alzheimer's disease (AD) by constrainingß-Amyloid (Aß) 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. LILRB4 expression and function in microglia has not been investigated. Here, we find that LILRB4 is highly expressed in microglia of patients with AD. Using mice that accumulate Aß andcarry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping Aß plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb)reduced Aß load,mitigated Aß-related behavioral abnormalities, enhanced microglia phagocytosis and attenuated expression of interferon-induced genes.In vitrobinding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction.In silicomodeling, 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. Overall design: To invest the blocking effect of anti-LILRB4 in vivo, we treat the ILT Telo Tg x 5XFAD mice with the Ctrl IgG2a or anti-LILRB4 for eight weeks and determine the amyloid pathology and microglia transcriptome at the end of the treatment.