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How the astrocytic urea cycle in the brain controls memory impairment in Alzheimer’s disease

Sequencing of RNA further metabolite analysis shows that the cyclic non-cyclic urea of ​​astrocytes is converted to cycling conditions in AD-like conditions. Credit: Basic Science Center

The number of elderly people with Alzheimer’s disease has been growing rapidly in recent years. For a long time, scientists believed that depleted amyloid-beta proteins accumulate and form plaques in the brain, leading to memory loss and neuronal death. However, the recent failure of clinical trials demonstrates the need for pressure to understand the missing link between amyloid-beta protein plaques and symptoms, a phenomenon that has been studied for many years.

Researchers led by Director C. Justin Lee from the Center for Cognition and Sociality at the Institute of Science Sciences (IBS), South Korea, are involved in this issue. Most recently in 2020, the group published in the magazine Nature of Neuroscience that stellar cells inside braincalled astrocytes, are very involved in Alzheimer’s disease and its development. As a result of this study, the team sought to further investigate the association of molecules under astrocytic responses.

After studying key cellular pathways and how they change in star-shaped neurons, the IBS team now finds a missing link: the amyloid-beta exchange to urea in the brain.

The urea cycle is widely studied and understood as a major lifeline in the liver and kidneys, as part of the digestive and digestive processes. In the liver, the urea cycle converts ammonia, a toxic product from protein digestion, into urea, which our kidneys excrete as easily as urine. Interestingly, previous studies have reported an increase in urea in the brains of Alzheimer’s patients, leading the IBS team to wonder if urea cycle plays a role in the pathology of the disease. disease. To their surprise, they discovered that the urea cycle was ‘activated’ in the stars of Alzheimer’s disease, in order to purify the amyloid-beta aggregates of toxins and remove them through urea.

However, this is not as useful as it sounds. The team found that activating the urea cycle results in the production of ornithine, a type of metabolite that accumulates in the cell and needs to be purified. Active astrocytes produce the enzyme ornithine decarboxylase 1 (ODC1) in this condition to counteract the accumulation of ornithine and convert it into putrescine. This therefore increases the levels of the neurotransmitter γ-aminobutyric acid (GABA), as well as toxic substances such as hydrogen peroxide (H).2BOTANY2) and ammonia in the brain.

Astrocytic urea in the brain controls memory impairment in Alzheimer's disease

PyrPeg, a compound that destroys amyloid-beta plaques, suggests that the astrocyte specificity of ODC1 reduces the amount of amyloid plaques in the AD (left) mouse model. The nerve block (upper right) by ODC1 is restored silently, as can be seen by the number of spikes produced on the needle now in the hippocampus. The recovery of memory loss can be seen in the improved function of ODC1-mute AD mouse in Mouse Test (bottom right). Credit: Basic Science Center

This ammonia further returns to the urea cycle and continues this process, resulting in further accumulation of nutrients. The major NEXT levels released by these stars play a role in inhibiting neuronal transmission, contributing to memory loss in Alzheimer’s disease.

In the study cited above for the 2020 group, hydrogen peroxide It was found to be the primary cause of the negative response of astrocytes to patients, resulting in cell death. Now, a new study from this study explains exactly how the GABA increase, H2BOTANY2, and ammonia contribute to and increase the memory loss and cell death associated with Alzheimer’s disease.

First author Ju Yeon Ha explains, “For years, scientists have been debating the benefits and harms of responsive astronomical work, and with this study, our team was able to determine the nature of the urea cycle. pros and cons of ornithine to putrescine and GABA, thus providing evidence of a variety of astrocytes in Alzheimer’s brain. “

The team is further experimenting to apply this new knowledge. They found that specific astrocyte inhibitors of the enzyme Ornithine Decarboxylase 1 in transgenic Alzheimer’s disease mice were able to inhibit the production of GABA and inhibit neuronal growth in the hippocampus of the mouse brain. These animals excel in memory-related behavioral activities, almost entirely recovering from AD-related memory loss after ODC1 stroke. In addition, the amount of amyloid-beta plaques is significantly reduced in the ODC1-shiru-shiru-shiru-shiru-shiru-shiru jinin shiru shiru shiru,,,,,, u re u u u u re u u u u re re re re re u u u re re re H.2BOTANY2GABA and ammonia.

Lee, the author of the study stated that “with the results of this study, we were finally able to integrate the pathway that binds amyloid-beta plaques to astrocytic activity, which discovers the presence of the urea cycle in reactive astrocytes for the first time. and found additional levels of the enzyme ODC1 in the brains of human AD patients, increasing the likelihood of translating the results from mouse research into humans and suggesting that ODC1 may be a new and potent therapeutic target for disease, preventing which can clear. amyloid-beta plaques and improve memory. “

This study is published in Molecules.


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Learn more:
Yeon Ha Ju et al, Astrocytic urea cycle detoxifies Aβ-derived ammonia while impaired memory in Alzheimer’s disease, Molecules (2022). DOI: 10.1016 / j.cmet.2022.05.011

hint: How astrocytic urea circulation in the brain manages memory damage in Alzheimer’s disease (2022, June 22) Retrieved 22 June 2022 from https://medicalxpress.com/news/2022-06-astrocytic-urea- brain-memory-impairment. html

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