Molecular Glue Degraders Enhance CAPRIN1-Dependent Lysosomal Degradation of APP and Reduce Amyloid β in Alzheimer's Disease.

The amyloid cascade involving the production and deposition of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP) is a leading hypothesis in the pathogenesis of Alzheimer's disease (AD). However, disease-modifying therapies targeting this cascade remain an unmet challenge. Here, we identify small molecules that degrade APP and reduce Aβ production through a targeted protein degradation strategy. Using genetically engineered APP cell models and induced pluripotent stem cell (iPSC)-derived neurons from patients with AD, we demonstrate that cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1) is expressed in neurons and physically interacts with APP. Screening of a CAPRIN1-targeted compound library identified compound 0043, which promotes intracellular APP degradation and reduces extracellular Aβ release. Structure-activity relationship optimization of 0043 derivatives yielded compound 0152 with improved potency and blood-brain barrier permeability. In AD iPSC-derived neurons, these compounds enhance CAPRIN1-APP interactions and promote CAPRIN1-dependent APP degradation through the endolysosomal pathway. CAPRIN1 is predominantly expressed in neurons in AD postmortem brains and iPSC-derived brain organoids. Systemic administration of compound 0152 significantly reduced APP levels, Aβ production, and amyloid burden in 5xFAD mice. These findings establish CAPRIN1-dependent, lysosome-targeted molecular glue degraders as a potential APP-targeted therapeutic strategy for AD.