At two months of age, the mice exhibited exceptional navigational skills. By six months, they were utterly disoriented. In the presence of bright lights they instinctively detested, they roamed a circular platform featuring 20 holes, unable to recall which one provided an escape route. The typical mice exited within three minutes. These mice could not locate it whatsoever.
What changed was neither a severe injury nor an infection. A lone enzyme had been eliminated from their brains, which is responsible for producing hydrogen sulfide, the gas that gives rotten eggs their offensive odor. However, at microscopic levels in neurons, this gas functions as a quiet protector of memory. When researchers at Johns Hopkins Medicine genetically deleted the enzyme responsible for its production, the brains of the mice began to degrade in a manner strikingly similar to Alzheimer’s disease.
The enzyme, cystathionine gamma-lyase or CSE, is now being recognized as a potential target for treating a condition that impacts over six million Americans. Published on December 26 in the Proceedings of the National Academy of Sciences, the research indicates that this protein plays a crucial role not just in cognition but also in sustaining the brain’s capacity for self-protection and repair.
When the Brain Ceases to Produce Its Own Defense
The gradual deterioration reflects what occurs in human neurodegeneration. Mice lacking CSE functioned normally during early life, implying the enzyme does not cause developmental issues. The cognitive decline occurred later, as the animals aged without the protective gas their neurons required.
Under electron microscopes, the damage became apparent. The blood-brain barrier, which shields the brain from toxins in circulation, exhibited significant gaps and breaches. Iron accumulated in brain tissue. DNA damage increased. These are the same alarming indicators pathologists observe in Alzheimer’s patients.
“This latest research suggests that CSE is a significant contributor to cognitive function and could pave the way for new treatment modalities in Alzheimer’s disease,” says Solomon Snyder, professor emeritus of neuroscience at Johns Hopkins.
The absence of the enzyme also halted neurogenesis, the brain’s process of generating new neurons in the hippocampus. In healthy brains, these new cells migrate to necessary areas and assist in forming new memories. Without CSE, that production line ceased. The molecular signals that initiate cell generation, such as CREB and brain-derived neurotrophic factor, remained inactive.
A Gas Too Toxic to Inject, but Crucial for Production
Hydrogen sulfide cannot be directly employed as a treatment due to its toxic effects at elevated doses. The identification of CSE as the main production mechanism provides an alternative approach: enhance or stabilize the enzyme itself, allowing the brain to safely manage its protective gas.
Lead researcher Bindu Paul, an associate professor at Johns Hopkins, indicated that oxidative stress and compromised barrier function were observable at various levels. The CSE-deficient mice exhibited symptoms correlating with clinical observations in Alzheimer’s progression, suggesting the enzyme plays a pivotal role upstream of numerous protective systems.
Existing Alzheimer’s therapies do little to halt decline, usually concentrating on plaques and tangles after considerable damage has taken place. Targeting CSE signals a transition towards preserving the brain’s innate repair mechanisms before cognitive decline sets in. If treatments can sustain this enzyme’s activity, they may preserve the intricate processes that enable neurons to communicate, adapt, and persist into old age.
The spatial memory assessment revealing the mice’s deterioration, the Barnes maze, is deceptively straightforward. Animals utilize visual signals to recall an escape route learned previously. When that memory fades despite intact vision and movement, something fundamental has disrupted the brain’s capacity to retain the past. By pinpointing what fails, the Johns Hopkins team may have discovered a means to preserve those memories.
[Proceedings of the National Academy of Sciences: 10.1073/pnas.2528478122](https://doi.org/10.1073/pnas.2528478122)
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