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Researchers identified small molecule inhibitors that target ILT3 (LILRB4), a protein that restricts microglial function and amyloid plaque clearance in Alzheimer's disease. Using affinity selection-mass spectrometry, they discovered compounds that bind ILT3 with nanomolar affinity and disrupt its interaction with ApoE, leading to restored amyloid uptake in human microglia. In a mouse model of Alzheimer's disease, pharmacological ILT3 inhibition improved cognitive function, reduced amyloid burden, and decreased neuroinflammation.
Why it matters
This work establishes ILT3 as a druggable target for Alzheimer's disease treatment, offering a new therapeutic approach that enhances the brain's innate immune response to clear amyloid plaques. The discovery of small molecule inhibitors provides a foundation for developing novel Alzheimer's therapies targeting neuroimmune checkpoints rather than amyloid directly.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Leukocyte immunoglobulin-like receptor B4 (LILRB4/ILT3) is an emerging neuroimmune checkpoint that restricts microglial activation and amyloid clearance in Alzheimers disease (AD) through ApoE-dependent signaling. Here, we establish ILT3 as a tractable small molecule target using affinity selection-mass spectrometry (AS-MS) to identify direct binders. Biophysical validation confirmed high-affinity engagement, with LT12 exhibiting nanomolar binding by MST and SPR. Computational modeling and mutagenesis defined a discrete ILT3 binding pocket, revealing a distributed interaction network critical for ligand engagement. Targeting ILT3 disrupted the ILT3-ApoE interaction, with LT12 showing potent inhibition in orthogonal biochemical assays. In human iPSC-derived microglia, ILT3 modulation attenuated SHP1/2 signaling, suppressed NF-{kappa}B activation, reduced IL-1{beta} secretion, and restored A{beta} uptake. In vivo, pharmacological targeting of ILT3 improved cognition, reduced amyloid burden, and attenuated neuroinflammation in 5xFAD mice. Together, these findings validate ILT3 as a drug-gable neuroimmune checkpoint and support its therapeutic targeting in AD.