Abstract
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.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (Grant No.81901295 to Y.Y, No. 82001137 to Yanlu Y. and No. 82071188 to Y.U.L.), Natural Science Foundation of Guangdong Province (Grant No. 2020A1515010228 to Y.Y.), Medical Scientific Research Foundation of Guangdong Province, China (Grant No. A2018046 to C.C. and No. A2019002 to Yanlu Y.), and the Science Foundation of Guangzhou First People’s Hospital (Grant No. Q2019015 to Yanlu Y.)
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YY, XR, and YUL designed the experiments; YanluY, CL, CC, and YL performed the experiments and analyzed the data. YY, XR, and YUL wrote the manuscript.
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Ying, Y., Lu, C., Chen, C. et al. SIRT3 Regulates Neuronal Excitability of Alzheimer’s Disease Models in an Oxidative Stress-Dependent Manner. Neuromol Med 24, 261–267 (2022). https://doi.org/10.1007/s12017-021-08693-9
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DOI: https://doi.org/10.1007/s12017-021-08693-9