Jung, S.; Jaiswal, N.; Rai, R. K.; Takagi, Y.; Lo, H.-Y.; Gao, C.; Zeng, L.; Wang, X.; Wohlford, R. K.; Higgins, R.; Bellail, A. C.; Hao, C.

INTRODUCTION: The amyloid cascade of amyloid {beta} (A{beta}) production from amyloid precursor protein (APP) plays a key role in the pathogenesis of Alzheimer disease (AD). However, disease-modifying therapies to disrupt this amyloid cascade remain an unmet challenge. METHODS: Using neurons and organoids differentiated from induced pluripotent stem cells (iPSCs) derived from sporadic and familiar AD patients, we identified small-molecule degraders that reduce A{beta} through screening of our library of cytoplasmic activation/proliferation-associate protein 1 (CAPRIN1)-targeted small-molecules. RESULTS: The small-molecule degraders act as molecular glues that bind CAPRIN1 and APP and enhance the protein-protein interaction. Tracking CAPRIN1 and APP in neurons revealed that the degraders induce CAPRIN1-mediated APP degradation through the endosomal-lysosomal pathway and thus reduce Abeta; peptide production in AD iPSC neurons and extracellular deposition in AD iPSC organoids. DISCUSSION: The small-molecule degraders provide new therapeutics through targeted protein degradation of APP and disruption of the amyloid cascade in AD brain.