Alzheimer’s disease (AD) is the most common cause of aging-related dementia. One potential therapeutic target is the gaseous signaling molecule hydrogen sulfide, which is depleted in patients with AD and protects neurons in rodent models of the disease, but the underlying molecular mechanisms have not been clear.

The authors provide evidence that hydrogen sulfide inhibits the activity of an enzyme called glycogen synthase kinase 3β (GSK3β), thereby decreasing the magnitude of tau hyperphosphorylation—a major neurotoxic hallmark of AD.

The authors report that normal Tau, but not the mutant version of the protein, binds to cystathionine γ-lyase (CSE). This neuronal enzyme synthesizes hydrogen sulfide and signals through sulfhydration of target proteins.

The results also reveal that CSE decreases Tau phosphorylation via GSK3β. Both CSE levels and sulfhydration are reduced in a mouse model of AD and in cerebral cortex brain tissue from patients with the disease.

Treatment of the mouse model with a compound that releases hydrogen sulfide protects against deficits in locomotor activity and memory. According to the authors, the findings shed light on a potential therapeutic strategy for aging-related dementia, including the most prominent form, AD. 

https://www.pnas.org/content/118/4/e2017225118