bioRxiv : the preprint server for biologyJul 10, 2026

Detailed CRISPR Study of the WAVE Complex Finds Drugs That Affect Movement of Brain Immune Cells Linked to Alzheimer’s

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Updated Jul 14, 2026

Abstract

Perturbation of NCKAP1L, CYFIP1, and BRK1 impaired migration in human THP-1 myeloid cells.

Genetic factors associated with Alzheimer's disease converge on microglial pathways, which influence cell behavior.
Diverse effects were observed among WAVE regulatory complex (WRC) paralogs concerning cell migration.
Specific regions within CYFIP1 and NCKAP1L were linked to migration, with a notable regulatory hotspot identified in CYFIP1.
NCKAP1L was found to be enriched in microglia across various states, indicating its potential role in disease.
Machine learning predicted Montelukast sodium and Piperacetazine as modulators of chemokine-directed migration, confirmed through experiments.

Simplified

Although genetic risk for Alzheimer's disease (AD) strongly converges on microglial pathways, the druggable functional protein regions that control disease-relevant microglial behaviors remain largely unknown. Here, we applied dense CRISPR-Cas9 mutagenesis and CRISPRtile-based functional mapping to the WAVE regulatory complex (WRC), a central regulator of actin remodeling and cell migration. In a pooled CCL2-directed migration assay in human THP-1 myeloid cells, perturbation of NCKAP1L , CYFIP1 , and BRK1 impaired migration and revealed divergent effects among WRC paralogs. Residue-level analysis mapped discrete migration-associated functional regions within CYFIP1 and NCKAP1L, including a CYFIP1 regulatory hotspot and a prioritized NCKAP1L region nominated for pharmacological targeting. Human single-nucleus datasets identified NCKAP1L as a microglia-enriched WRC component expressed across diverse microglial states. Machine-learning-guided compound prediction nominated Montelukast sodium and Piperacetazine, which we experimentally validated as negative and positive modulators of chemokine-directed migration, respectively. These findings establish WRC-dependent migration as a pharmacologically tunable myeloid process relevant to AD.

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Detailed CRISPR Study of the WAVE Complex Finds Drugs That Affect Movement of Brain Immune Cells Linked to Alzheimer’s

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