Researchers look to the stars for new Alzheimer's target

To help crack Alzheimer's disease, researchers are looking to a North Star—or, more accurately, a star-shaped cell in the brain that could play a role in progression of the neurodegenerative disease. 

New findings shed light on the role astrocytes—star-shaped cells in the brain involved in Alzheimer’s disease progression—play in memory loss and neuronal cell death for patients with the disease. The findings, along with a related mouse model, illuminate a path to a new potential therapeutic target for Alzheimer’s patients.

While scientists have long thought misfolded groups of amyloid beta protein form plaques in the brain, leading to memory loss and neuronal death in Alzheimer’s patients, recent clinical trial fails underscore the need to better understand the link between these plaques and the disease. Now, researchers from the Center for Cognition and Sociality within the Institute for Basic Science in South Korea believe they have found that link, according to findings published in Cell Metabolism June 22.

While past studies have detected increased urea—a compound produced from ammonia that can be excreted in the urine—in the brain of Alzheimer’s patients, the team in South Korea uncovered the urea cycle in reactive astrocytes for the first time. The scientists found the digestive and excretory process converts amyloid beta to urea in the brain. The findings reveal that the urea cycle is switched on in the astrocytes of the brain among Alzheimer’s disease patients to clean up toxic amyloid beta groups and remove them in the form of urea.

However, the process is a bit counterintuitive, as turning on the cycle also triggers the production of ornithine, which must be cleaned up. When orinithine accumulates, astrocytes release the enzyme ornithine decarboxylase 1 (ODC1) to convert it to putrescine, which, in turn, produces neurotransmitter γ-aminobutyric acid (GABA) as well as toxic byproducts such as hydrogen peroxide and ammonia in the brain.

The newly created ammonia feeds back into the urea cycle and starts the process all over again, causing more toxic byproducts to build up. The high levels of GABA released by astrocytes then stop neuronal transmission, contributing to Alzheimers’ hallmark memory loss.

“For years, scientists have been debating about the beneficial and detrimental role of reactive astrocytes, and with the findings of this study, our group is able to clearly demarcate the beneficial urea cycle and the detrimental conversion of ornithine to putrescine and GABA, thereby providing evidence of the dual nature of astrocytes in Alzheimer’s disease brain,” author Ju Yeon Ha, Ph.D., said in a news release.

The researchers didn’t stop there, though. In an Alzheimer’s mice model, the scientists found that astrocyte-specific gene silencing of ODC1 could stop excessive GABA production and neuronal inhibition in the hippocampus. After shutting down ODC1, the mice performed better in memory-related behavioral tasks, almost completely recovering from disease-related loss of memory.  

If translated in human models, ODC1 could be a new therapeutic target against Alzheimer’s disease, according to the researchers.