AdipoRon promotes amyloid‐β clearance through enhancing autophagy via nuclear GAPDH‐induced sirtuin 1 activation in Alzheimer's disease

Abstract Background and Purpose Amyloid‐ β (A β ) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of A β . Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of A β and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects A β clearance remain unclear. Experimental Approach We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. Key Results AdipoRon promotes A β clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased A β deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. Conclusion and Implications AdipoRon promotes the clearance of A β by enhancing autophagy through the AdipoR1/AMPK‐dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.