Honokiol improves cognitive impairment in APP/PS1 mice through activating mitophagy and mitochondrial unfolded protein response

Activated Mitophagy and mitochondrial unfolded protein response (UPR^mt) has been reported to protect against mitochondrial dysfunction, which is closely related to the onset of Alzheimer's disease (AD). Honokiol (HKL, C₁₈H₁₈O₂) is a kind of natural extraction from bark of Magnolia officinalis with anti-AD effect, and our study aims to explore the effect of HKL on Mitophagy and UPR^mt in AD. Briefly, male APP/PS1 mice and Aβ oligmer (AβO)-treated primary hippocampal neurons were respectively used to mimic AD in vivo and in vitro. It was determined that HKL significantly ameliorated cognitive impairment and synaptic damages in APP/PS1 mice. Besides, the activated Mitophagy and UPR^mt together with inhibited oxidative stress and improved mitochondrial dynamic disorder were further validated in hippocampus of HKL-treated APP/PS1 mice. Meanwhile, HKL-treated mice displayed much higher hippocampal expression and activity of mitochondrial Sirtuin 3 (SIRT3). Therefore, SIRT3 knockdown was further achieved in primary hippocampal neurons by effective shRNA, and we determined that HKL improved synaptic damage, mitochondrial dysfunction, Mitophagy and UPR^mt in AβO-treated primary hippocampal neurons in a SIRT3-dependent manner. In summary, our study validates the protective effect of HKL on AD, and highlights that HKL exerts anti-AD effect by activating Mitophagy and UPR^mt.