Expression of sirtuin type 3 in locus ceruleus is associated with long-term intermittent hypoxia-induced neurocognitive impairment in mice.

Abstract

Recent studies revealed that increased oxidative stress is one of the major mechanisms underlying the cognitive dysfunction induced by long-term intermittent hypoxia (LTIH). Locus ceruleus (LC) neurons, which fire at high rate across wakefulness, are essential for optimal cognitive function. The aim of this study was to investigate whether sirtuin type 3 (SirT3), a redox responses coordinator, plays a role in LTIH-induced neurocognitive impairment. Mice were subjected to LTIH or room air [normal control (NC)] for 10 weeks (10 h/day). Morris water maze test was used to detect spatial learning and memory ability. The oxidative stress was evaluated through the level of superoxide dismutase 2 (SOD2) and dihydroethidium and ethidium (DHE). Then the correlation between the number of platform crossing and SirT3 content measured by western blot was analyzed. Results showed that performance on the Morris water maze test was significantly worse for LTIH mice than for NC mice. LTIH exposure downregulated SirT3 and SOD2 in LC neurons, increasing DHE immunodensity. In addition, the SirT3 protein levels in LC neurons were positively related to the number of platform crossing. These observations suggest that SirT3-SOD2-intracellular superoxide is a key component associated with the cognitive dysfunction induced by LTIH. Moreover, they lend support to a rational basis for targeting upregulation of SirT3 in LC as a disease modifying strategy.Video abstract: http://links.lww.com/WNR/A577.