Overview: Study reveals the role of the urea cycle in the brain and examines the dual nature of astrocytes in the brains of people with Alzheimer’s disease.
Source: Institute of Basic Sciences
The number of elderly people with Alzheimer’s disease has risen rapidly in recent decades. For a long time, scientists believed that misfolded aggregates of amyloid beta protein accumulate and form plaques in the brain, leading to memory loss and neuronal death.
However, the recent failures of the clinical trials point to the urgent need to understand the missing link between amyloid beta protein plaques and the symptoms of the disease, a phenomenon that has been studied for decades.
Researchers led by Director C. Justin Lee of the Center for Cognition and Sociality within the Institute for Basic Science (IBS), South Korea, have delved extensively into this topic. Recently in 2020 the group published in the magazine 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 elevated urea levels in the brains of Alzheimer’s patients, prompting 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 is ‘turned on’ to clear 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 levels of the neurotransmitter -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 increased 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 that “scientists have debated for years the beneficial and adverse roles of reactive astrocytes, and with the findings of this study, our group is able to study 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 less in ODC1 gene-silenced mouse brains, indicating that the urea cycle worked more efficiently to remove the accumulated protein without the accumulation of harmful byproducts such as H.2O2GABA and ammonia.
Lee, the study’s corresponding author noted that “with the results of this study, we were finally able to delineate the pathway linking amyloid beta plaques to astrocytic reactivity, establishing for the first time the presence of a functional urea cycle in reactive astrocytes.” brought to light…
“We also found elevated levels of the 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 against the disease. whose inhibition could remove amyloid-beta plaques and improve memory.”
About this research news on Alzheimer’s disease
Original research: Closed access.
†Astrocytic urea cycle detoxifies Aβ-derived ammonia and impairs memory in Alzheimer’s diseaseby Yeon HaJu et al. cell metabolism
Astrocytic urea cycle detoxifies Aβ-derived ammonia and impairs memory in Alzheimer’s disease
Alzheimer’s disease (AD) is one of the major neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and marked progressive memory loss. In AD, astrocytes are proposed to take up and remove Aβ plaques. However, how Aβ induces pathogenesis and memory impairment in AD remains elusive.
We report that normal astrocytes show a non-cyclic urea metabolism, while Aβ-treated astrocytes show an switched-on urea cycle with upregulated enzymes and accumulated incoming metabolite aspartate, starting substrate ammonia, final product urea and byproduct putrescine.
Gene silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitates the conversion of ornithine to putrescine, stimulates the urea cycle and eliminates aberrant putrescine and its toxic byproducts ammonia and H2O2 and the end product GABA to recover from reactive astrogliosis and memory impairment in AD.
Our findings imply that the astrocytic urea cycle plays an opposite role of beneficial Aβ detoxification and adverse memory impairment in AD. We propose ODC1 inhibition as a promising therapeutic strategy for AD to facilitate the removal of toxic molecules and prevent memory loss.
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