A Newly Synthesized Rhamnoside Derivative Alleviates Alzheimer's Amyloid-β-Induced Oxidative Stress, Mitochondrial Dysfunction, and Cell Senescence through Upregulating SIRT3

Oxidative stress-induced mitochondrial dysfunction and cell senescence are considered critical contributors to Alzheimer's disease (AD), and oxidant/antioxidant imbalance has been a therapeutic target in AD. SIRT3 is a mitochondrial protein regulating metabolic enzyme activity by deacetylation and its downregulation is associated with AD pathology. In the present study, we showed that a newly synthesized rhamnoside derivative PL171 inhibited the generation of reactive oxidant species (ROS) induced by amyloid-β(42) oligomers (Aβ(42)O), major AD pathological proteins. Moreover, the reduction of mitochondrial membrane potential (MMP) and the impairment of mitochondrial oxygen consumption triggered by Aβ(42)O were also prevented by PL171. Further experiments demonstrated that PL171 reduced the acetylation of mitochondrial proteins, and particularly the acetylation of manganese superoxide dismutase (MnSOD) and oligomycin-sensitivity-conferring protein (OSCP), two mitochondrial SIRT3 substrates, was suppressed by PL171. Mechanism studies revealed that PL171 upregulated SIRT3 and its upstream peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) under basal and Aβ(42)O-treated conditions. The inhibition of SIRT3 activity could eliminate the protective effects of PL171. Further, long-term treatment with Aβ(42)O increased the number of senescent neuronal cell, which was also alleviated by PL171 in a SIRT3-dependent manner. Taken together, our results indicated that PL171 rescued Aβ(42)O-induced oxidative stress, mitochondrial dysfunction, and cell senescence via upregulating SIRT3 and might be a potential drug candidate against AD.