Small Amounts of Hydrogen Sulfide Improved Alzheimer’s Signs in Mice, Johns Hopkins Finds

Hydrogen Sulfide May Protect Aging Neurons and Reverse Some Alzheimer’s Features in Mice

Researchers at Johns Hopkins Medicine report that low, sustained doses of hydrogen sulfide (H₂S) improved cognitive and motor deficits in mice engineered to model Alzheimer’s disease. The findings, published in the Proceedings of the National Academy of Sciences (PNAS), suggest that physiological levels of H₂S help maintain protein signaling in the brain and that restoring those levels can reverse some disease-associated changes in this animal model.

“Our new data firmly link aging, neurodegeneration and cell signaling using hydrogen sulfide and other gaseous molecules within the cell,” said study lead author Dr. Bindu Paul.

The human body naturally produces small amounts of H₂S that participate in cellular signaling. The Johns Hopkins team focused on a biochemical modification called sulfhydration, in which H₂S chemically alters target proteins and affects their function. The researchers report that sulfhydration levels decline with age and are reduced in brains affected by Alzheimer’s disease.

To test whether restoring H₂S could change disease outcomes, the investigators treated Alzheimer’s-model mice with NaGYY, a compound that slowly releases hydrogen sulfide. Over a 12-week period, treated mice showed roughly a 50% improvement on combined measures of cognitive and motor performance compared with untreated model mice. Treated animals were better at spatial-memory tasks and were generally more active.

Follow-up experiments identified a likely molecular mechanism involving glycogen synthase kinase 3 beta (GSK3β). Under healthy H₂S levels, GSK3β activity and its interactions with other proteins are regulated by sulfhydration. When H₂S is low, GSK3β binds more strongly to the Tau protein, promoting Tau aggregation into intracellular clumps that disrupt neural communication and contribute to neuron death — a hallmark of Alzheimer’s pathology. The authors show that restoring H₂S reduced this harmful interaction in the mouse brains.

“Understanding the cascade of events is important to designing therapies that can block this interaction like hydrogen sulfide is able to do,” said Ph.D. student Daniel Giovinazzo, first author of the study.

Important caveats: These results are preclinical and come from an animal model. H₂S is toxic at high concentrations, and NaGYY or related approaches must be rigorously tested for safety, dosing, and efficacy in humans before any clinical use. The study provides a promising mechanistic insight and a potential therapeutic direction, but it does not mean H₂S supplementation is safe or effective for people with Alzheimer’s disease at this time.

The authors note that improved chemical tools to deliver low, sustained amounts of H₂S were key to this work, and they call for further studies to evaluate translational potential.