SIRT3 Regulates Neuronal Excitability of Alzheimer’s Disease Models in an Oxidative Stress-Dependent Manner

Mitochondrial deacetylase Sirtuin-3 (SIRT3) has been shown to regulate metabolic and antioxidant functions. Previous studies have reported that SIRT3 mediates change of neuronal excitability. However, the underlying mechanism is unclear. Here, we show that SIRT3 deficiency results in neural hyperactivity, decreased survival rate, and increased oxidative stress of culture neurons, while a superoxide dismutase 2 mimetic reduces oxidative stress and suppresses the neuronal hyperactivity. In culture neurons treated with Aβ, SIRT3 activator reduces level of reactive oxygen species (ROS) and hyperactivity of neurons while increasing level of ROS restores the neuronal hyperactivity. Utilizing two photon in vivo brain imaging, we show that inhibition of SIRT3 results in elevated neuronal excitatory in an animal model of Alzheimer's disease of early stage, whereas suppression of the ROS level reverses it. These findings demonstrate an oxidative stress-dependent role of SIRT3 in regulation of neuronal excitability in Alzheimer's disease.