Scientists at Johns Hopkins Medicine have identified a protein, Cystathionine γ-lyase (CSE), as a key factor in memory formation and potential target for Alzheimer’s disease treatment. The findings come from a study funded by the National Institutes of Health and published on December 26 in the Proceedings of the National Academy of Sciences.
The research focused on genetically engineered mice lacking the CSE enzyme, which is known for producing hydrogen sulfide gas in the brain. Bindu Paul, M.S., Ph.D., associate professor at Johns Hopkins University School of Medicine and lead author of the study, explained that this protein is critical for memory formation.
Previous studies had suggested that hydrogen sulfide could protect neurons in mice, but its toxicity at high doses has prevented direct use as a therapy. The current research aimed to better understand how to safely maintain low levels of this gas within neurons.
Mice without the CSE enzyme exhibited memory and learning loss, increased oxidative stress, DNA damage, and compromised blood-brain barrier integrity—symptoms associated with Alzheimer’s disease. According to Paul, “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,” said co-corresponding author Solomon Snyder, M.D., D.Sc., D.Phil., who retired from Johns Hopkins Medicine faculty in 2023.
The team used behavioral tests such as the Barnes maze to compare spatial memory between normal mice and those lacking CSE. At two months old, both groups performed similarly; however, by six months old, only normal mice retained their ability to find shelter quickly.
First author Suwarna Chakraborty noted: “The decline in spatial memory indicates a progressive onset of neurodegenerative disease that we can attribute to CSE loss.”
Further analysis showed reduced expression of proteins related to neurogenesis in mice lacking CSE. Electron microscope images revealed significant damage to blood vessels and difficulties for new neurons migrating to regions important for forming memories.
Co-first author Sunil Jamuna Tripathi stated: “The mice lacking CSE were compromised at multiple levels, which correlated with symptoms that we see in Alzheimer's disease.”
Alzheimer’s affects over 6 million people in the United States according to data from the U.S. Centers for Disease Control and Prevention (CDC), with no cure or consistently effective treatments currently available.
Funding came from several sources including grants from NIH (1R01AG071512 among others), Department of Defense (HT94252310443), American Heart Association AHA-Allen Initiative in Brain Health and Cognitive Impairment, Solve ME/CFS Initiative, Catalyst Award from Johns Hopkins University, Valour Foundation, Wick Foundation, Department of Veterans Affairs Merit Award (I01BX005976), Louis Stokes Cleveland Department of Medical Affairs Veterans Center, Mary Alice Smith Funds for Neuropsychiatry Research, Lincoln Neurotherapeutics Research Fund; Gordon and Evie Safran Neuropsychiatry Fund; Leonard Krieger Fund of Cleveland Foundation.
In addition to Paul and Snyder, contributors included Richa Tyagi and Benjamin Orsburn from Johns Hopkins; Edwin Vázquez-Rosa et al. from Case Western University; Thibaut Vignane and Milos Filipovic from Leibniz Institute for Analytical Sciences; Sudarshana Sharma from Hollings Cancer Center; Bobby Thomas from Darby Children's Research Institute/Medical University of South Carolina; Zachary Weil and Randy Nelson from West Virginia University School of Medicine.
