2023/12/29 by Sunghan Jung, Raktim Roy, Xu Wang +12 · 1 voice
Medicine · Neuroscience · Biochemistry, Genetics and Molecular Biology · #Alzheimer's disease research and treatments #Nuclear Receptors and Signaling #Genetics and Neurodevelopmental Disorders
paper · pdf · doi:10.1101/2023.12.29.573648
openalex publication_date 2023/12/29 · openalex created_date 2023/12/30 · openalex updated_date 2026/07/27
Abstract Overexpression of amyloid precursor protein (APP) is a key driver of amyloid β (Aβ) pathology, making APP a compelling therapeutic target in Alzheimer’s disease (AD). Here, we identify small molecules that selectively degrade APP in human neurons through a targeted protein degradation approach. Structural analyses reveal that these compounds act as molecular glues, binding at the interface between cytoplasmic activation/proliferation-associate protein 1 (CAPRIN1) and APP and stabilizing their interaction within a ternary complex. In neurons derived from induced pluripotent stem cells (iPSCs) from sporadic and familial AD patients, these compounds promote CAPRIN1-dependent degradation of both wild-type and mutant APP through the endo-lysosomal pathway. The lead compound, 0152, is blood-brain barrier permeable, and its administration significantly reduces Aβ production and amyloid burden in the brains of 5xFAD mice. These findings demonstrate that molecular glue degraders harness the CAPRIN1-dependent lysosomal pathway for selective APP degradation, offering a targeted therapeutic strategy for AD.