Degradation of Alzheimer’s Amyloid-β by a Catalytically Inactive Insulin Degrading Enzyme

Insulin-degrading-enzyme (IDE) is a key target to treat type-2 diabetes, and also known to clear Alzheimer’s amyloid-β (Aβ). However, the development of catalytically inactive IDE mutant (IDE) could risk Aβ clearance. Here, we demonstrate Aβ degradation by IDE and the removal of zinc from the toxic Aβ-Zn complex enabling proteolysis by IDE. Fluorescence and NMR results show delays in Aβ aggregation by both wild-type and IDE in their zinc-bound and unbound states. Diffusion NMR and LC-MS revealed the delayed kinetics is due to Aβ degradation. Remarkably, IDEs exhibited no proteolysis against zinc bound Aβ species as evidenced from high-speed AFM, electron microscopy, chromatography and NMR. On the other hand, zinc removal from the Zn-Aβ complex enabled the proteolysis by IDEs. These findings highlight the role of zinc in switching on/off the proteolysis of Aβ and urge the development potent zinc chelators as a strategic alternative therapeutic for AD.