Astrocytic urea cycle controls memory impairment in Alzheimer's

Wednesday, 06 July, 2022

Astrocytic urea cycle controls memory impairment in Alzheimer's

South Korean researchers have revealed the urea cycle in astrocytes as the link between amyloid-beta accumulation and memory loss, uncovering a potential therapeutic target to treat Alzheimer’s disease in the process. Their research has been published in the journal Cell Metabolism.

For a long time, scientists have believed that Alzheimer’s disease (AD) is caused by misfolded aggregates of amyloid-beta protein that accumulate and form plaques in the brain, leading to memory loss and neuronal death. However, the recent failures of the clinical trials indicate the pressing need to understand the missing link between amyloid-beta protein plaques and the disease’s symptoms, a phenomenon that has been studied for decades.

Researchers led by Director C Justin Lee from the Center for Cognition and Sociality within Korea’s Institute for Basic Science (IBS) have delved extensively into this topic. In 2020, the group discovered that the star-shaped cells in the brain, called astrocytes, are greatly involved in AD and its progression. The group sought to further explore the molecular connection underlying the astrocytic response, and now they have found the missing link: the conversion of amyloid-beta to urea in the brain.

The urea cycle is understood as a major metabolic pathway in the liver and kidneys, as a part of our digestive and excretory processes. In the liver, the urea cycle converts ammonia, a toxic product from protein digestion, into urea, which is easily excreted by our kidneys as urine. Previous studies have reported increased urea in the brain of AD patients, which led the IBS team to wonder if the urea cycle played any role in the pathology of the disease. To their surprise, they found that the urea cycle is ‘switched on’ in the astrocytes of the AD brain, in order to clean up the toxic amyloid-beta aggregates and remove them in the form of urea.

This isn’t as beneficial as it sounds. The group found that the switching on of the urea cycle causes the production of ornithine, another metabolite that accumulates in the cell and needs to be cleaned up. The hardworking astrocytes produce the enzyme ornithine decarboxylase 1 (ODC1) in this condition to deal with the accumulated ornithine and convert it to putrescine. This consequently increases the levels of neurotransmitter γ-aminobutyric acid (GABA), as well as toxic by-products like hydrogen peroxide (H2O2) and ammonia in the brain.

This ammonia further feeds back into the urea cycle and continues this process, causing more and more accumulation of toxic by-products. High levels of GABA released by these astrocytes play an inhibitory action on neuronal transmission, contributing to the loss of memory in AD.

In the group’s 2020 study, hydrogen peroxide was found to be the primary factor causing the severe reactivity of diseased astrocytes, causing neuronal cell death. The findings from their latest study precisely explain how the increased GABA, H2O2 and ammonia contribute to and exacerbate the loss of memory and neuronal cell death associated with AD.

“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,” said first author Yeon Ha Ju.

Experimenting further, the group found that astrocyte-specific gene silencing of ODC1 in a transgenic AD mouse model was able to stop the excessive GABA production and neuronal inhibition in the hippocampus of the mouse brain. These animals performed better in memory-related behavioural tasks, almost completely recovering from the AD-associated loss of memory after ODC1 knockdown. Additionally, the number of amyloid-beta plaques was significantly fewer in ODC1-gene silenced mouse brains, indicating that the urea cycle was working more efficiently to clear the accumulated protein without causing the accumulation of harmful by-products such as H2O2, GABA and ammonia.

“With the results from this study, we were able to finally delineate the pathway linking amyloid-beta plaques to astrocytic reactivity, uncovering the presence of a functional urea cycle in reactive astrocytes for the first time,” Lee said.

“We also found increased levels of enzyme ODC1 in human AD patients’ brains, raising the possibility of translating the results from our mouse study to humans and indicating that ODC1 may be a novel and powerful therapeutic target against the disease, inhibition of which could clear amyloid-beta plaques as well as improve memory.”

Image credit: ©

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