Scientists at Johns Hopkins Medicine say results of a new National Institutes of Health-funded study are advancing efforts to exploit a new target for Alzheimer's disease: a protein that manufactures an important gas in the brain.
Experiments conducted in genetically engineered mice reinforce that the protein, Cystathionine γ-lyase, or CSE — ordinarily known for producing hydrogen sulfide gas responsible for the foul smell of rotten eggs — is critical for memory formation, says Bindu Paul, M.S., Ph.D. , associate professor of pharmacology, psychiatry and neuroscience at the Johns Hopkins University School of Medicine, who led the study.
The new research, published Dec. 26 in Proceedings of the National Academy of Sciences , were designed to better understand the basic biology of the protein, and its value as a novel target for drugs that boost the expression of CSE in people to help keep brain cells healthy and slow neurodegenerative disease.
Previous studies have pointed to hydrogen sulfide as a protector of neurons in mice, Paul says. But because the gas is toxic at high doses and therefore not safe for direct use in the brain, researchers must work to better understand how to safely maintain levels of this gas at the infinitely small levels present in neurons, the scientists say.
The new work shows that mice genetically engineered to lack the CSE enzyme experience memory and learning loss and exhibit increased oxidative stress, DNA damage and compromised blood-brain barrier integrity — hallmarks of Alzheimer's disease, says Paul, the paper's corresponding author.
These recent experiments grew out of a 2014 report from the laboratory of Solomon Snyder, M.D., D.Sc., D.Phil. , professor emeritus of neuroscience, pharmacology, and psychiatry, in which CSE was shown to benefit brain health in mice with Huntington's disease. For this, scientists used genetically engineered mice lacking the CSE protein, originally generated in 2008, when CSE was shown to be important for vascular function and blood pressure regulation . In 2021, the team showed that CSE malfunctioned in mice with Alzheimer's disease and that miniscule amounts of hydrogen sulfide injections helped protect brain health.
Those previous studies, however, were conducted in mice genetically engineered with other mutations known to cause neurodegenerative disease and did not focus on CSE by itself.
"This most recent work indicates that CSE alone is a major player in cognitive function and could provide a new avenue for treatment pathways in Alzheimer's disease," says co-corresponding author Snyder, who retired from the Johns Hopkins Medicine faculty in 2023.
Using the same line of CSE-lacking mice from the 2008 study in this recent study, scientists compared the spatial memory (ability to remember directions and follow cues) in CSE-lacking mice and in normal mice.
In the experiments, scientists placed mice on a platform known as the Barnes maze, in which the mice learned to seek shelter when a bright light appeared. At the age of two months, both the CSE-lacking mice and normal mice avoided the bright light and consistently found the shelter within a three-minute period. At the age of six months, however, these CSE-lacking mice were unable to find the escape route, while normal six-month-old mice continued to do so.
"The decline in spatial memory indicates a progressive onset of neurodegenerative disease that we can attribute to CSE loss," says first author Suwarna Chakraborty, a researcher in Paul's lab.
Disruptions in the formation of new neurons in the hippocampus region of the brain (critical to learning and memory) are thought to be a hallmark of neurodegenerative disease, the scientists say. Using biochemical and analytical techniques, the researchers determined that neurogenesis-related proteins were expressed less often or not at all in mice lacking CSE when compared with normal mice.
Then, using high powered electron microscopes, the scientists observed the brains of CSE-lacking mice and found big breaks in blood vessels, indicating that they had suffered damage to the blood-brain barrier, another symptom seen in people with Alzheimer's disease. Furthermore, new neurons had a difficult time migrating to the hippocampus region, where they would ordinarily help form new memories.
"The mice lacking CSE were compromised at multiple levels, which correlated with symptoms that we see in Alzheimer's disease," says co-first author Sunil Jamuna Tripathi, a researcher in Paul's lab.
More than 6 million people in the United States have Alzheimer's disease, according to the U.S. Centers for Disease Control and Prevention, and prevalence is on the rise. To date, there are no cures or treatments that have been proven to consistently slow disease progression. Harnessing CSE and its production of hydrogen sulfide could be an avenue for therapeutic benefit, the scientists say.
Funding support for this research was provided by the National Institutes of Health (1R01AG071512, P50 DA044123,1R21AG073684, O1AGs066707, U01 AG073323, AG077396, NS101967, NS133688, P01CA236778), the Department of Defense (HT94252310443), the American Heart Association, AHA-Allen Initiative in Brain Health and Cognitive Impairment, the Solve ME/CFS Initiative, the Catalyst Award from Johns Hopkins University, the Valour Foundation, the Wick Foundation, Department of Veterans Affairs Merit Award (I01BX005976), the Louis Stokes Cleveland Department of Medical Affairs Veterans Center, the Mary Alice Smith Funds for Neuropsychiatry Research, the Lincoln Neurotherapeutics Research Fund, the Gordon and Evie Safran Neuropsychiatry Fund; and the Leonard Krieger Fund of the Cleveland Foundation.
In addition to Paul, Snyder, Chakraborty and Tripathi, other scientists who contributed to this work include Richa Tyagi and Benjamin Orsburn from Johns Hopkins; Edwin Vázquez-Rosa, Kalyani Chaubey, Hisashi Fujioka, Emiko Miller and Andrew Pieper of Case Western University; Thibaut Vignane and Milos Filipovic from Leibniz Institute for Analytical Sciences, Germany; Sudarshana Sharma from Hollings Cancer Center; Bobby Thomas from Darby Children's Research Institute and the Medical University of South Carolina, and Zachary Weil and Randy Nelson from West Virginia University School of Medicine.
