Mechanisms of Hydrogen Sulfide against the Progression of Severe Alzheimer’s Disease in Transgenic Mice at Different Ages

<b><i>Backgroud:</i></b> Alzheimer disease is an age-related severe neurodegenerative pathology. The level of the third endogenous gas, hydrogen sulfide (H₂S), is decreased in the brain of Alzheimer’s disease (AD) patients compared with the brain of the age-matched normal individuals; also, plasma H₂S levels are negatively correlated with the severity of AD. Recently, we have demonstrated that systemic H₂S injections are neuroprotective in an early phase of preclinical AD. <b><i>Objectives:</i></b> This study focuses on the possible neuroprotection of a chronic treatment with an H₂S donor and sulfurous water (rich of H₂S) in a severe transgenic 3×Tg-AD mice model. <b><i>Method:</i></b> 3×Tg-AD mice at 2 different ages (6 and 12 months) were daily treated intraperitoneally with an H₂S donor and sulfurous water (rich of H₂S) for 3 months consecutively. We investigated the cognitive ability, brain morphological alterations, amyloid/tau cascade, excitotoxic, inflammatory and apoptotic responses. <b><i>Results:</i></b> Three months of treatments with H₂S significantly protected against impairment in learning and memory in a severe 3×Tg-AD mice model, at both ages studied, and reduced the size of Amyloid β plaques with preservation of the morphological picture. This neuroprotection appeared mainly in the cortex and hippocampus, associated with reduction in activity of c-jun N-terminal kinases, extracellular signal-regulated kinases and p38, which have an established role not only in the phosphorylation of tau protein but also in the inflammatory and excitotoxic response. <b><i>Conclusion:</i></b> Our findings indicate that appropriate treatments with various sources of H₂S, might represent an innovative approach to counteract early and severe AD progression in humans.