Molecular hydrogen attenuates sepsis-induced cognitive dysfunction through regulation of tau phosphorylation

Sepsis-associated encephalopathy (SAE) is a cognitive dysfunction caused by sepsis. Hyperphosphorylated tau is considered to play a significant role in the progression of neurodegenerative disease and also contributes to cognitive dysfunction in septic mice. Molecular hydrogen (H2) plays an antioxidant and anti-inflammatory role, and plays a protective role in septic mice. This study explored the possible effects of H2 on cognition and tau phosphorylation in a mouse model of SAE.The model of sepsis was established in C57BL/6J male mice by cecal ligation and puncture surgery. Mice treated with 2 % H2 inhalation for 60 min at 1 h and 6 h after surgery, respectively. HY-15769, the inhibitor of Tau Tubulin Kinase 1 (TTBK1), was injected 1 h before the surgery. The 7-day survival rates of the mice were recorded. Cognitive behavior was tested with both novel object recognition and the Y-maze novelty arm recognition on day 7 after surgery. Hematoxylin-eosin staining was used to observe the histological damage in CA1 region of hippocampus. The expression of inflammatory factors in hippocampus was assessed by Elisa. Western blotting was adopted to determine the tau phosphorylation levels at AT8 epitopes (pSer202 and pThr205) and T22 epitopes (neurofibrillary tangle protein oligomer), and the GSK3β phosphorylation levels (Tyr216), as well as p-Ser422 and TTBK1 levels in the hippocampus. The number of dendritic spine and mushroom type of dendritic spines in the hippocampus were assessed by Golgi staining.The survival rate, visual and spatial learning ability, and memory ability were improved in septic mice treated with H2. After H2 treatment, the density of dendritic spine, mushroom type of dendritic spine, and the number of normal hippocampal neurons were progressively elevated. H2 decreased the levels of phosphorylated tau protein, tau oligomer and TTBK1, as well as the phosphorylation of tau key kinase. Furthermore, the injection of HY-15769 (a TTBK1 inhibitor) protected SAE through the similar way.The protective effect of H2 on cognitive dysfunction induced by SAE may be achieved by inhibiting tau phosphorylation, which is perhaps related with the inhibition of TTBK1.