Hydrogen sulfide improves spatial memory impairment and decreases production of Aβ in APP/PS1 transgenic mice

Abstract Alzheimer’s disease (AD) is defined both by its progressive cognitive deterioration and hallmark increase in neuronal Aβ plaque formation. However, many of the underlying neurobiological facets of this disease are still being elucidated. Previous research has demonstrated that production of neuronal hydrogen sulfide (H 2 S) is significantly decreased in patients with AD. Moreover, systemic plasma H 2 S levels are negatively correlated with its severity. However, how a decrease in H 2 S production might be correlated with either the etiology or pathophysiology of AD remains unknown. To better understand the role of H 2 S in AD, we examined both levels of H 2 S and the expression and activity H 2 S-synthesizing enzyme (cystathionine beta synthase or CBS) in an APP/PS1 transgenic mouse line at 3, 6, 9 and 12 months. After intraperitoneal (i.p.) administration of an H 2 S donor (NaHS) into APP/PS1 mice, application of exogenous H 2 S resulted in improved spatial learning and memory acquisition in APP/PS1 mice. H 2 S administration also led to significant decrease in extracellular levels of Aβ40 and Aβ42, the expression of BACE1 and PS1, and a significant increase of ADAM17 expression. Similarly, an increase in non-amyloidogenic C83 fragment generation and a decrease in amyloidogenic C99 fragment generation were also observed. Thus, NaHS application resulted in a shift from the plaque-forming beta pathway to the non-plaque forming alpha pathway of APP cleavage in 6 and 12 month APP/PS1 mice. These results indicate the importance of H 2 S to AD severity and that administration of exogenous H 2 S can promote a non-amyloidogenic processing of APP.