Stop and Smell the Rotten Eggs: How Hydrogen Sulfide Protects the Brain From Alzheimer’s Disease

Despite being intricately involved in the creation of primordial life on Earth eons ago, hydrogen sulfide was previously thought to be solely a noxious environmental toxin that reeks of rotten eggs. Recently, the gaseous compound improved its image, as researchers discovered that the human body produces — and benefits from — hydrogen sulfide in moderate amounts. One of the leading areas of hydrogen sulfide research is with neurodegenerative disorders, including Alzheimer’s disease. That's because it’s known that people with Alzheimer’s disease have lower hydrogen sulfide activity and metabolism, but the reasons why and how to reverse it remained largely unknown — until now. 

Published January 2021 in the journal PNAS, a collaborative research team out of Johns Hopkins University School of Medicine and the University of Exeter in the United Kingdom developed a novel way to slowly deliver just the right amount of hydrogen sulfide, improving various aspects of Alzheimer’s disease in mice. If these results were successfully translated to humans, this innovative hydrogen sulfide delivery system could potentially treat or prevent cognitive decline.

How hydrogen sulfide harnesses healthier brains 

One of the hallmark characteristics of Alzheimer’s disease is an accumulation of the protein tau, which aggregates in the brain to block communication between neurons. Normal tau proteins are connected to microtubules — hollow structures that maintain cell structure and facilitate movement. However, when tau is exposed to abnormal chemical changes called hyperphosphorylation, it detaches from the microtubules, losing its proper location and clumping together with other tau proteins, becoming toxic to the brain. 

In addition to tau aggregates from hyperphosphorylation, Alzheimer’s disease can develop from high amounts of oxidative stress in the brain, which involves excessive amounts of inflammatory and damaging compounds called reactive oxygen species (ROS). One way the brain regulates oxidative stress is through a pathway called reverse transsulfuration. This pathway plays a central role in sulfur metabolism and oxidative stress regulation in cells and is the only route for biosynthesis of the amino acid cysteine in mammals. It also produces the antioxidant glutathione. The cysteine generated by reverse transsulfuration then synthesizes more glutathione and sulfur-containing compounds, including hydrogen sulfide. Although cysteine is highly susceptible to oxidative stress, adequate amounts of hydrogen sulfide can prevent this from happening, creating a positive feedback loop of increased cysteine, glutathione, and hydrogen sulfide with decreased oxidative stress.

Hydrogen sulfide is a natural gaseous signaling molecule created in small amounts inside almost all human tissues. Though the compound is most often recognized as the foul-smelling gas that resembles rotten eggs, hydrogen sulfide is actually thought to protect against Alzheimer’s disease. As a signaling compound, hydrogen sulfide regulates many cellular processes through sulfhydration — a chemical action that changes specific proteins’ behavior by adding a sulfur molecule to them. As sulfhydration activity tends to decrease with age and plays a role in the development of neurodegenerative diseases, increasing hydrogen sulfide in the body is thought to be neuroprotective.

Releasing hydrogen sulfide into the body, Goldilocks style

In this study, Giovinazzo and colleagues injected 6-month-old mice that were genetic models of Alzheimer’s disease with a hydrogen sulfide-carrying compound called NaGYY. This synthetic chemical donates hydrogen sulfide molecules in a unique way, allowing the compound to be slowly released into the body, rather than all at once. While low amounts of hydrogen sulfide contribute to aging and neurological disorders, excessive amounts of hydrogen sulfide can be toxic to the brain. Researchers have previously not known how to slowly add hydrogen sulfide into the body. That is, until now, with NaGYY providing a Goldilocks-amount stream of the compound — not too much, not too little, but just the right amount. 

Not just a stinky smell: hydrogen sulfide improves markers of Alzheimer’s disease 

After 12 weeks of daily injections of NaGYY or a placebo compound, the mice underwent tests of memory and motor function, in addition to measurements for various markers of sulfhydration and reverse transsulfuration. The brains of mice with Alzheimer’s disease that went untreated had reduced activity of CSE, an enzyme that synthesizes hydrogen sulfide and cysteine, indicating dysfunctional reverse transsulfuration pathways. Additionally, the untreated cognitively impaired mice also had high levels of an enzyme called glycogen synthase β (GSK3β). In the absence of hydrogen sulfide, this enzyme increases the hyperphosphorylation and clumping of tau proteins. But when hydrogen sulfide is present, the rotten egg-smelling compound donates sulfur molecules (sulfhydrates) to GSK3β, allowing the enzyme to do its regular job in cell signaling. 

Conversely, the mice who were treated with the hydrogen sulfide-containing compound experienced reversals to these markers, including the increased donation of sulfur molecules to GSK3β and boosted CSE activity, indicating restoration of their sulfhydration pathway and ability to synthesize cysteine. NaGYY treatment also mitigated the decline in the reverse transsulfuration pathway activity seen in the Alzheimer’s diseased mice, reducing the amount of ROS accumulation in the brain. To sum it up in one sentence, hydrogen sulfide prevents harmful tau aggregation by adding sulfur groups to GSK3β, inhibiting its inclination to hyperphosphorylate tau. 

Hydrogen sulfide and cognition, from mice to humans

While all of these benefits to molecular markers of neurodegeneration were promising, the researchers next needed to assess any behavioral or cognitive improvements in the NaGYY-treated mice with Alzheimer’s disease. After the 12-week NaGYY treatment, these mice had restored locomotor activity. Although motor dysfunction is a common symptom of Alzheimer’s disease, it’s often overlooked in research. Additionally, the hydrogen sulfide-containing compound improved memory and cognitive function by 50% compared to mice who didn’t receive NaGYY treatment. 

This study potentially opens doors for more drugs or treatments involving targeted hydrogen sulfide delivery in neurodegenerative diseases. However, while these results are significant for mice, we still don’t know for sure if slowly boosting hydrogen sulfide levels will help humans with Alzheimer’s disease. And, keep in mind that hydrogen sulfide requires a delicate balance to be beneficial, so don’t go sticking your head in a sewer in the hopes of boosting your brain. 

References: 

Giovinazzo D, Bursac B, Sbodio JI, et al. Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation. Proc Natl Acad Sci U S A. 2021;118(4):e2017225118. doi:10.1073/pnas.2017225118

Paul BD, Snyder SH. Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol. 2018;149:101-109. doi:10.1016/j.bcp.2017.11.019