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

Authors

Sunghan Jung, Xu Wang, Bin Liu, Raktim Roy, Nancy Jaiswal, Ratan K Rai, Yuichiro Takagi, Cen Gao, Lifan Zeng, Ho-Yin Lo, Reagan K Wohlford, Ryan K Higgins, Bruce T Lamb, Anantha Shekhar, Anita C Bellail, Chunhai Hao

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77575. Sep 01, 2026. Epub Sep 01, 2026.

Abstract

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.

PMID:
42681755
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.

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