On May 23, 2025, Professor Dong Zhifang's team from the Affiliated Children's Hospital of Chongqing Medical University published a research paper titled "Disruption of BAG3-mediated BACE1 Stabilization Alleviates Neuropathology and Memory Deficits in a Mouse Model of Alzheimer's Disease" in Science Advances.

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the central nervous system, with complex pathogenesis and a lack of effective treatments.
The study found that BAG3 forms a ternary complex with HSP70 and BACE1, inhibiting the ubiquitin-proteasome degradation and autophagy-lysosome pathways of BACE1, thereby maintaining its stability and promoting Aβ production. Based on this discovery, the team successfully identified the specific binding site between BACE1 and BAG3 and developed a novel Tat-BACE1 polypeptide drug. This drug competitively binds to BAG3, effectively blocking the BAG3-BACE1 interaction and significantly reducing BACE1 protein levels and Aβ production. Animal experiments confirmed that this therapeutic strategy markedly improved synaptic and cognitive functions in AD model mice.

This study not only elucidates the molecular mechanism by which BAG3 regulates BACE1 stability but also provides a new approach for AD treatment. The developed Tat-BACE1 polypeptide drug exhibits strong targeting and high safety, showing significant translational potential for AD prevention and treatment.
Full Article Link:
https://www.science.org/doi/10.1126/sciadv.adt7981
(Translated by AI)