Targeting the CSE enzyme could open up new avenues for treating Alzheimer's disease

Targeting the CSE enzyme could open up new avenues for treating Alzheimer's disease

Scientists at Johns Hopkins Medicine say results from a new study funded by the National Institutes of Health advance efforts to exploit a new target for Alzheimer's disease: a protein that produces an important gas in the brain.

Experiments conducted on genetically modified mice show that the protein cystathionine γ-lyase, or CSE—normally known for producing hydrogen sulfide gas, responsible for the foul smell of rotten eggs—is crucial for memory formation, says Bindu Paul, MS, Ph.D., associate professor of pharmacology, psychiatry and neuroscience at Johns Hopkins University School of Medicine, who led the study.

The new study was published on December 26thProceedings of the National Academy of Scienceswere designed to better understand the protein's basic biology and its value as a new target for drugs that increase the expression of CSE in humans to help keep brain cells healthy and slow neurodegenerative diseases.

Previous studies have suggested that hydrogen sulfide protects the neurons of mice, Paul says. But because the gas is toxic in high doses and therefore not safe for direct use in the brain, researchers need to better understand how to safely maintain the infinitesimal concentrations of this gas present in neurons, the scientists say.

The new work shows that genetically engineered mice lacking the CSE enzyme suffer memory and learning loss and have increased oxidative stress, DNA damage and impaired blood-brain barrier integrity - hallmarks of Alzheimer's disease, says Paul, the study's corresponding author.

These recent experiments grew out of a 2014 report from the laboratory of Solomon Snyder, MD, D.Sc., D.Phil., professor emeritus of neuroscience, pharmacology and psychiatry, showing that CSE promotes brain health in mice with Huntington's disease. To do this, scientists used genetically engineered mice that lacked the CSE protein, which was originally created in 2008 when it emerged that CSE was important for vascular function and blood pressure regulation. In 2021, the team showed that CSE did not work in mice with Alzheimer's and that tiny amounts of hydrogen sulfide injections helped protect brain health.

However, these previous studies were conducted on genetically modified mice with other mutations known to cause neurodegenerative diseases and did not focus on CSE as such.

“This recent work shows that CSE alone plays an important role in cognitive function and may provide a new avenue for treatment pathways in Alzheimer's disease,” says co-author Snyder, who retired from Johns Hopkins University School of Medicine in 2023.

Using the same line of CSE-deficient mice from the 2008 study, scientists in this current study compared spatial memory (ability to remember instructions and follow cues) in CSE-deficient mice and normal mice.

In the experiments, scientists placed mice on a platform known as a Barnes maze, where the mice learned to seek shelter when a bright light appeared. At two months of age, both the mice without CSE and the normal mice avoided bright light and always found shelter within three minutes. However, at six months of age, these CSE-deficient 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 a neurodegenerative disease that we can attribute to CSE loss,” says lead author Suwarna Chakraborty, a researcher in Paul’s lab.

Disturbances in the formation of new neurons in the hippocampus region of the brain (crucial for learning and memory) are considered a hallmark of neurodegenerative diseases, according to the scientists. Using biochemical and analytical techniques, the researchers found that neurogenesis-related proteins were expressed less often or not at all in mice without CSE compared to normal mice.

Scientists then used powerful electron microscopes to examine the brains of CSE-deficient mice and found large tears in the blood vessels, suggesting they had suffered damage to the blood-brain barrier, another symptom common to people with Alzheimer's disease. In addition, new neurons had difficulty migrating to the hippocampus region, where they would normally help form new memories.

“The mice lacking CSE were impaired on multiple levels, which correlated with the symptoms we see in Alzheimer's disease,” says co-first author Sunil Jamuna Tripathi, a researcher in Paul's lab.

According to the U.S. Centers for Disease Control and Prevention, more than 6 million people in the United States have Alzheimer's disease and the prevalence is increasing. To date, there are no cures or treatments that have been proven to permanently slow the progression of the disease. Harnessing CSE and its production of hydrogen sulfide could be an avenue for therapeutic benefit, the scientists say.

Financial support for this research was provided by the National Institutes of Health (1R01AG071512, P50 DA044123,1R21AG073684, O1AGs066707, U01 AG073323, AG077396, NS101967, NS133688, P01CA236778) and the Department of Defense (HT94252310443), the American Heart Association, the AHA-Allen Initiative in Brain Health and Cognitive Impairment, the Solve ME/CFS Initiative, the Johns Hopkins University Catalyst Award, the Valor Foundation, the Wick Foundation, the 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 of Johns Hopkins; Edwin Vázquez-Rosa, Kalyani Chaubey, Hisashi Fujioka, Emiko Miller and Andrew Pieper of Case Western University; Thibaut Vignane and Milos Filipovic from the Leibniz Institute for Analytical Sciences, Germany; Sudarshana Sharma of 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.

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