Hydrogen Sulfide Attenuates Learning And Memory Impairment And Its Underlying Mechanisms In AD Mice

Objective: This study was designed to investigate the spatial learning and memory effect of hydrogen sulfide(H2S) on overexpressing human amyloid precursor protein(APP695swe) and presenilin-1(PS1-d E9) transgenic mice model of AD, and further explore its potential mechanisms.Methods: Nine months male APP/PS1 transgenic mice(n=30) were randomly divided into two groups: APP/PS1+NS(nomal saline, NS) and APP/PS1+Na HS(Na HS, a donor H2S) groups. Age-matched male wild-type(WT) littermates(n=20) were randomly divided into two groups: WT+NS and WT+Na HS groups. Na HS-treated groups were consumed with Na HS at the dose of 2.8 mg/kg/d, however, WT+NS and APP/PS1+NS groups were afforded volume-matched NS. After intraperitoneal injection three months(from 9 to 12 months of age), spatial learning and memory ability was determined by Morris water maze. In addition, thioflavin S staining and Nissl staining were employed to assess the effect of Na HS on amyloid plaques contents and neuronal death in mice. The protein expression of cystathionine-β-synthase(CBS), 3-mercaptopyruvate-sulfurtransferase(3MST), amyloid precursor protein(APP), β-site APP-cleaving enzyme1(BACE1), nuclear factor-erythroid 2-related factor2(Nrf2), heme oxygenase-1(HO-1) and glutathione s-transferase(GST) were measured by Western blot, also Aβ1-40 and Aβ1-42 contents.Results: Compared with WT+NS group, the mean escape latency was markedly increased and the time percentage in target quardrant showed notable decrease in APP/PS1+NS group. The number of neurons were significantly reduced in hippocampal CA3 and DG regions. The amyloid plaques, Aβ1-40, Aβ1-42 contents, and the protein expression of APP and BACE-1 were increased, meanwhile, the protein expression of CBS, 3MST, Nrf2, HO-1 and GST were dramatically decreased in the hippocampus and cortex in APP/PS1+NS group. These effects in WT+Na HS group showed no notable differences compared to the WT+NS group. However, compared with APP/PS1+NS group, the mean escape latency was decreased and the time percentage in target quardrant was notably increased in APP/PS1+Na HS. Moreover, the number of neurons were significantly increased in hippocampal CA3 and DG regions. Furthermore, the amyloid plaques, Aβ1-40, Aβ1-42 contents, APP, BACE-1 expression were decreased in the hippocampus and cortex, the protein expression of Nrf2, HO-1 and GST were significantly increased in APP/PS1+Na HS.Conclusion: Based on our experimental conditions, H2 S ameliorates spatial learning and memory impairment, decreases the numbers of senile plaques in APP/PS1 transgenic AD mice. The underlying mechanisms of defense may be related with the increase of the levels of CBS-H2 S and 3MST-H2 S, prevention production of APP- Aβ and the activation of Nrf2 signaling pathway, suggesting that H2 S may be an effective agent on AD treatment.