A Newly Synthesized Rhamnoside Derivative Alleviates Alzheimer'S Amyloid-Beta-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-beta(42) oligomers (A beta O-42), major AD pathological proteins. Moreover, the reduction of mitochondrial membrane potential (MMP) and the impairment of mitochondrial oxygen consumption triggered by A beta O-42 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-gamma coactivator 1 alpha (PGC-1 alpha) under basal and A beta O-42-treated conditions. The inhibition of SIRT3 activity could eliminate the protective effects of PL171. Further, long-term treatment with A beta O-42 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 A beta O-42-induced oxidative stress, mitochondrial dysfunction, and cell senescence via upregulating SIRT3 and might be a potential drug candidate against AD.