“Rotten egg” protein is a potential therapeutic target for Alzheimer’s

Alzheimer’s treatment has proven a hard egg to crack, but harnessing a protein that produces hydrogen sulfide could be a viable therapeutic option.

Recent research led by scientists at Johns Hopkins University School of Medicine (MD, USA) has identified a potential new therapeutic target for Alzheimer’s disease – one that smells rotten. Combining genetic, proteomic, biochemical and behavioral approaches, the team has shed light on a hydrogen sulfide-producing protein’s role in cognition.

Cystathionine γ-lyase (CSE), the enzyme responsible for synthesizing the amino acid cysteine and the gas hydrogen sulfide – of rotten egg fame – also has an important role to play in neuroprotection, we’re beginning to understand. The protein declines with age and is dysregulated in a number of neurodegenerative diseases, including Alzheimer’s and Huntington’s disease.

Previously, CSE was considered more prominent in peripheral tissues, while another protein, cystathionine β-synthase, was thought to be the principal enzyme governing hydrogen sulfide signaling in the brain. This new study adds to a growing body of evidence that challenges that assumption, hinting that CSE may be pivotal for cognitive function – although its specific involvement has yet to be characterized.

To investigate further, the team genetically ablated the enzyme in mice and then compared spatial memory in CSE-lacking (Cth^−/−) and wildtype mice using the Barnes maze. The rodents were exposed to bright light and tasked with locating an escape box. At 2 months old, both groups were able to do so, but by 6 months, Cth^−/− were significantly impaired, indicating a decline in spatial memory.

The researchers also performed global proteomic profiling of the hippocampi of the mice, identifying 800 to 900 proteins that were significantly altered in Cth^−/− mice relative to wildtype controls. This was followed by gene ontology analysis, focusing on biological processes and cellular components, which, respectively, revealed that transport proteins and synaptic proteins were most affected by the loss of CSE.

Further pathway enrichment analysis using the Kyoto encyclopedia of genes and genomes highlighted perturbations in pathways linked to neurodegeneration and reactive oxygen species in mice lacking CSE.

Meanwhile, immunostaining demonstrated that CSE depletion elevates DNA damage in the hippocampus and transmission electron microscopy showed that the blood–brain barrier appears to deteriorate in Cth^−/− mice – something commonly associated with cognitive decline. This was backed up by Western blot analysis and immunohistochemistry.

“The mice lacking CSE were compromised at multiple levels, which correlated with symptoms that we see in Alzheimer’s disease,” concluded co-first author Sunil Jamuna Tripathi.

The research answers a longstanding question surrounding CSE’s role in brain function and identifies CSE as a potential therapeutic target for brain health.

As co-corresponding author Solomon Snyder explained: “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.”