The astrocytic urea cycle in brain controls memory loss in Alzheimer’s disease

June 22, 2022 11:29 PM IST

daejeon [South Korea], Jun 22 (ANI): The number of elderly people with Alzheimer’s disease has increased rapidly in recent decades. For a long time, scientists believed that misfolded aggregates of amyloid beta protein accumulated and formed plaques in the brain, leading to memory loss and death of nerve cells. However, recent clinical trial failures indicate an urgent need to understand the missing link between amyloid beta protein plaques and disease symptoms.
This is a phenomenon that has been studied for decades. Researchers led by C. Justin LEE, director of the Center for Cognition and Sociality within the Korea Institute for Fundamental Sciences (IBS), have explored this topic extensively.
Recently in 2020, the group published in the journal Nature Neuroscience that the star-shaped cells in the brain, called astrocytes, are heavily involved in Alzheimer’s disease and its progression. Driven by this discovery, the group sought to further investigate the molecular connection underlying the astrocytic response.
After studying basal cellular pathways and how they morph into the brain’s star-shaped astrocytes, the IBS team has now found the missing link: the conversion of amyloid beta to urea in the brain.
The urea cycle is widely studied and is considered an important metabolic pathway in the liver and kidneys, as 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. Surprisingly, previous studies have reported an increase in urea in the brains of patients with Alzheimer’s disease, leading the IBS team to question whether the urea cycle played a role in the pathology of the disease. To their surprise, they found that the urea cycle in the astrocytes of the Alzheimer’s brain has been ‘turned on’ to clear out and remove the toxic amyloid-beta aggregates in the form of urea.

However, this is not as beneficial as it sounds. The group found that turning on the urea cycle triggers the production of ornithine, another metabolite that builds up in the cell and needs to be cleaned up. The hard-working astrocytes in this state produce the enzyme ornithine decarboxylase 1 (ODC1) to deal with the accumulated ornithine and convert it into putrescine. This consequently increases the levels of the neurotransmitter g-aminobutyric acid (GABA), as well as toxic byproducts such as hydrogen peroxide (H2O2) and ammonia in the brain.
This ammonia feeds further into the urea cycle, continuing this process, accumulating more and more toxic byproducts. High levels of GABA released by these astrocytes inhibit neuronal transmission, contributing to the telltale memory loss in Alzheimer’s disease.
In the group’s aforementioned 2020 study, hydrogen peroxide was found to be the primary factor causing the severe reactivity of diseased astrocytes, which causes neuronal cell death. Now, the new findings of this study explain exactly how the elevated GABA, H2O2, and ammonia contribute to and exacerbate the loss of memory and neuronal cell death associated with Alzheimer’s disease.
First author JU Yeon Ha stated, “For years, scientists have debated the beneficial and detrimental roles of reactive astrocytes, and with the findings of this study, our group is able to investigate the beneficial urea cycle and the deleterious conversion of ornithine to putrescine and GABA, providing evidence of the dual nature of astrocytes in the Alzheimer’s brain.”
The group continued to experiment to exploit this new knowledge. They found that astrocyte-specific gene silencing of the enzyme Ornithine Decarboxylase 1 in a transgenic mouse model for Alzheimer’s disease could stop the excess GABA production and neuronal inhibition in the hippocampus of the mouse brain. These animals performed better in memory-related behavioral tasks and recovered almost completely from AD-associated amnesia after ODC1 knockdown. In addition, the number of amyloid-beta plaques was significantly lower in mouse brains that silenced the ODC1 gene, indicating that the urea cycle worked more efficiently to remove the accumulated protein without causing the accumulation of harmful byproducts such as H2O2, GABA and ammonia. .
Director C. Justin LEE, the corresponding author of the study noted, “With the results of this study, we were able to finally delineate the pathway linking amyloid beta plaques to astrocytic reactivity, detecting the presence of a functional urea cycle in reactive astrocytes.We also found elevated levels of enzyme ODC1 in the brains of human AD patients, increasing the possibility of translating the results of our mouse study to humans and indicating that ODC1 may be a novel and potent therapeutic target. are against the disease, inhibiting which amyloid beta plaques can be removed and memory improved.”
This research is published in Cell Metabolism, a CellPress journal with a strong impact factor of 27.28. Due to the importance and novelty of the study, lead author Dr. JU Yeonha invited to present the findings at the journal Metabolites in Signaling and Disease symposium in April in Lisbon, Portugal. (ANI)

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