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Small-molecule degraders reduce Aβ production through CAPRIN1-mediated lysosomal degradation of APP in Alzheimer iPSC-derived neurons

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.

2023-12-29 neuroscience
10.1101/2023.12.29.573648 bioRxiv
Show abstract

Overexpression of amyloid precursor protein (APP) is a key driver of amyloid {beta} (A{beta}) pathology, making APP a compelling therapeutic target in Alzheimers 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 A{beta} 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.

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