The inhibitory microglial receptor LILRB4 (ILT3) suppresses amyloid-beta clearance in Alzheimers disease (AD) through ApoE-dependent signaling but remains undrugged by small molecules. Here, we report the AI-guided discovery of small molecule inhibitors that directly disrupt the LILRB4-ApoE interaction. Ultralarge-scale screening of ~500 million compounds identified small molecules that bind LILRB4 with nanomolar affinity and competitively block ApoE engagement, as validated across orthogonal biophysical assays. Structural and mutational analyses define a tractable interdomain pocket that mediates ligand recognition. In human iPSC-derived microglia, LILRB4 inhibition suppresses SHP1/2-dependent signaling, attenuates NF-kB activation, and restores A{beta} uptake. The lead compound exhibits favorable pharmacokinetics with robust brain penetration and, upon oral administration, improves cognitive performance, reduces amyloid burden, and dampens neuroinflammation in the 5xFAD mouse model. These findings establish LILRB4 as a druggable neuroimmune checkpoint and demonstrate that small molecule disruption of inhibitory microglial signaling can restore disease-relevant function in vivo.
Abdel-Rahman, S., Gabr, M.
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