Hydrogen Sulfide Gas from CSE Protein Emerges as Potential Alzheimer’s Treatment Target

Researchers at Johns Hopkins University School of Medicine announced Tuesday that the enzyme cystathionine γ-lyase (CSE) and its production of hydrogen sulfide could serve as a new therapeutic target for Alzheimer’s disease. The team found that CSE helps prevent harmful Tau protein phosphorylation linked to cognitive decline by sulfhydrating the enzyme GSK3β, a process that is disrupted in aging and Alzheimer’s patients, according to their study.

The Johns Hopkins University research team found that cystathionine γ-lyase (CSE) prevents harmful phosphorylation of the Tau protein by sulfhydrating the enzyme glycogen synthase kinase 3 beta (GSK3β), a process that becomes disrupted with aging and in Alzheimer’s disease patients. This sulfhydration occurs at the Cys218 residue on GSK3β, located near the enzyme’s active site, according to the research.

The study showed that hydrogen sulfide (H2S) produced by CSE inhibits phosphorylation of Tau at the Ser396 site, which is associated with cognitive decline.

CSE, an enzyme previously thought to be mostly active in peripheral tissues such as the liver and kidney, was found to play a significant neuroprotective role in the brain. The enzyme catalyzes the production of H2S and cysteine from cystathionine, which itself is synthesized from homocysteine by cystathionine β-synthase (CBS). While CBS has been considered the primary source of H2S in the brain, the Johns Hopkins team’s findings challenge this assumption by demonstrating CSE’s involvement in cognitive functions and its decline in Alzheimer’s disease, according to co-first author Sunil Jamuna Tripathi.

In 2021, the researchers reported that mice lacking CSE exhibited Alzheimer’s-like symptoms, including cognitive deficits and increased DNA damage in the hippocampus. These CSE-deficient mice also showed deterioration of the blood-brain barrier, which is linked to neurodegeneration and cognitive impairment. The study employed genetic, proteomic, biochemical, and behavioral analyses to elucidate CSE’s role in brain health, officials said.

The team’s earlier experiments involved administering small doses of hydrogen sulfide to Alzheimer’s disease mouse models, which alleviated symptoms associated with CSE malfunction. For example, treatment with H2S donors such as AP39, administered at 100 nanomoles per kilogram in APP/PS1 mice, resulted in improved cognition, reduced brain atrophy, and decreased amyloid plaque levels. Similarly, intracerebroventricular injections of NaHS, another H2S donor, reduced hippocampal cell death in mouse models exposed to amyloid beta protein. GYY4137, a slow-releasing H2S donor, was shown to increase CSE activity and lower homocysteine levels in plaque models, according to the published data.

Plasma levels of hydrogen sulfide were found to be significantly reduced in patients with Alzheimer’s disease, vascular dementia, and cerebrovascular disease compared with healthy controls. A study analyzing postmortem brain tissue from 13 Alzheimer’s patients and six controls confirmed lower H2S concentrations in the diseased brains. Moreover, plasma H2S levels negatively correlated with disease severity in Alzheimer’s patients, suggesting a potential biomarker role. In contrast, CBS enzyme levels in Alzheimer’s brains did not differ significantly from those in normal brains, indicating that CSE’s decline may be more critical in disease progression, researchers noted.

Endogenous hydrogen sulfide is generated through four enzymatic pathways, including CBS, CSE, 3-mercaptopyruvate sulfurtransferase, and cysteine aminotransferase. While CBS is expressed in the brain, liver, and kidney and is regulated by molecules such as S-adenosyl-L-methionine, nitric oxide, and carbon monoxide, CSE is predominantly found in peripheral tissues but now recognized to have functional expression in the brain, according to biochemical analyses.

The study further identified that depletion of CSE in mice perturbed pathways related to neurodegeneration and reactive oxygen species, reinforcing the enzyme’s role in maintaining neuronal health. Immunostaining and transmission electron microscopy revealed that CSE contributes to blood-brain barrier integrity, which is essential for protecting the brain from toxic substances and maintaining homeostasis, according to the Johns Hopkins team.

Hydrogen sulfide signaling participates in various cellular processes through sulfhydration or persulfidation of target proteins, which modulates their activity. The research highlighted that H2S protects nerve function by influencing amyloid precursor protein metabolism and exerting anti-apoptotic, anti-inflammatory, and antioxidant effects. These mechanisms further support the therapeutic potential of targeting CSE and its H2S production in Alzheimer’s disease.

The findings challenge the long-standing view that CBS is the principal H2S-producing enzyme in the brain and instead position CSE as a critical regulator of cognitive function and neuroprotection. The research, conducted by Johns Hopkins University School of Medicine and published recently, advances the understanding of hydrogen sulfide’s role in brain health and identifies CSE as a promising target for therapeutic intervention in Alzheimer’s disease.