DKK3-LRP1 complex and a chemical inhibitor regulate Aβ clearance in models of Alzheimer’s disease

Impaired clearance of amyloid-β (Aβ) contributes to Alzheimer's disease (AD) pathogenesis, but its upstream modulators remain poorly defined. We report secreted Dickkopf (DKK) proteins-DKK1 through DKK4-as previously unrecognized ligands of low-density lipoprotein receptor-related protein 1 (LRP1), a principal Aβ clearance receptor. Analyses of cells derived from a patient with AD, postmortem tissue, and 5×FAD mice reveal that DKK1 and DKK3 are elevated in AD and reduce Aβ uptake and degradation in neurons and astrocytes. Mechanistically, DKKs inhibit Aβ clearance by competitively binding LRP1 and promoting its internalization. In 5×FAD mice, DKK3 overexpression worsens, while knockout improves, Aβ pathology and cognitive outcomes. A targeted high-throughput screen of ~3000 compounds identified SJ-300 as a potent and selective inhibitor of the DKK3-LRP1 interaction. SJ-300 restores Aβ clearance and rescues cognitive function and neuropathology in 5×FAD mice. These findings uncover DKK3-LRP1 axis as a contributor for Aβ metabolism and nominate SJ-300 as a promising therapeutic candidate for AD intervention.