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How the Astrocyte Urea Cycle in the Brain Controls Memory Impairment in Alzheimer’s Disease – Neuroscience News

Summary: Study reveals the role of the urea cycle in the brain and explores the dual nature of astrocytes in the brains of people with Alzheimer’s disease.

Source: Institute of Basic Sciences

The number of older people with Alzheimer’s disease has increased rapidly over the past few decades. For a long time, scientists believed that misfolded aggregates of beta-amyloid protein accumulate and form plaques in the brain, leading to memory loss and neuronal death.

However, recent clinical trial failures point to the pressing need to understand the missing link between amyloid beta plaques and disease symptoms, a phenomenon that has been studied for decades.

Researchers led by Director C. Justin Lee of the Center for Cognition and Sociality at the Institute of Basic Sciences (IBS) in South Korea have studied this subject at length. Recently in 2020, the group published in the journal Natural neuroscience that star-shaped cells in the brain, called astrocytes, are strongly implicated in Alzheimer’s disease and its progression.

Driven by this discovery, the group sought to further explore the molecular connection underlying the astrocyte response.

After studying the basic cellular pathways and their evolution in the star-shaped astrocytes of the brain, the IBS team has now found the missing link: the conversion of beta-amyloid to urea in the brain.

The urea cycle is widely studied and understood as a major 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 of 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 Alzheimer’s patients, leading the IBS team to wonder if the urea cycle plays a role. in the pathology of the disease. To their surprise, they found that the urea cycle was ‘turned on’ in Alzheimer’s brain astrocytes to clean up toxic amyloid-beta aggregates and eliminate them as urea.

However, this is not as beneficial as it seems. The group discovered that the activation of the urea cycle causes the production of ornithine, another metabolite which accumulates in the cell and must be cleaned.

Hard-working astrocytes produce the enzyme ornithine decarboxylase 1 (ODC1) in this condition to process accumulated ornithine and convert it into putrescine. This consequently increases levels of the neurotransmitter γ-aminobutyric acid (GABA), as well as toxic by-products like hydrogen peroxide (H2O2) and ammonia in the brain.

This ammonia feeds back into the urea cycle and continues this process, causing an ever-increasing build-up of toxic by-products. High levels of GABA released by these astrocytes play an inhibitory action on 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 diseased astrocytes to become severely reactive, causing neuronal cell death.

Now, the new findings from this study explain precisely how the increase in GABA, H2O2, and ammonia contribute to and exacerbate memory loss and neuronal cell death associated with Alzheimer’s disease.

First author Ju Yeon Ha said, “Scientists have been debating the beneficial and detrimental role of reactive astrocytes for years, and with the results of this study, our group is able to clearly delineate the beneficial cycle of urea and the detrimental conversion of ornithine to putrescine and GABA, thus providing evidence for the dual nature of astrocytes in the Alzheimer’s disease brain.

The group continued its experiments to exploit this new knowledge. They found that astrocyte-specific gene silencing of the enzyme ornithine decarboxylase 1 in a transgenic mouse model of Alzheimer’s disease was able to stop excessive GABA production and neuronal inhibition in the hippocampus of the brain. of the mouse. These animals performed better in memory-related behavioral tasks, recovering almost completely from AD-associated memory loss after the knockdown of ODC1.

Next-generation RNA sequencing and metabolite analysis reveal that non-cyclic urea metabolism of astrocytes transitions to a cyclic state under AD-like reactive conditions. Credit: Institute of Basic Sciences

In addition, the number of amyloid-beta plaques was significantly lower in the brains of mice silenced with the ODC1 gene, indicating that the urea cycle worked more efficiently to remove accumulated protein without causing the accumulation of sub -harmful products such as H2O2GABA and ammonia.

Lee, the study’s corresponding author, noted that “with the results of this study, we were able to finally delineate the pathway linking amyloid-beta plaques to astrocytic reactivity, revealing for the first time the presence of a functional urea cycle in reactive astrocytes.

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“We also found increased levels of the ODC1 enzyme in the brains of human Alzheimer’s disease patients, raising the possibility of translating the results of our mouse study to humans and indicating that the ODC1 could be a new and powerful therapeutic target against the disease, the inhibition of which could eliminate amyloid-beta plaques and improve memory.

About this Alzheimer’s disease research news

Author: Press office
Source: Institute of Basic Sciences
Contact: Press service – Institute for Basic Sciences
Image: Image is credited to the Institute for Basic Science

Original research: Access closed.
Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease” by Yeon Ha Ju et al. Cell metabolism


Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease

Alzheimer’s disease (AD) is one of the major neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and severe progressive memory loss. In AD, astrocytes are proposed to take up and clear Aβ plaques. However, how Aβ mediates pathogenesis and memory impairment in AD remains elusive.

We report that normal astrocytes exhibit non-cyclic urea metabolism, whereas Aβ-treated astrocytes exhibit an activated urea cycle with upregulated enzymes and accumulated inbound metabolite aspartate, from the starting ammonia, the final product urea and the secondary product putrescine.

Gene silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating the conversion of ornithine to putrescine, stimulates the urea cycle, and removes aberrant putrescine and its toxic byproducts ammonia and H2O2 and its end product GABA to recover from reactive astrogliosis and memory impairment in AD.

Our results imply that the astrocytic urea cycle exerts opposing roles of beneficial Aβ detoxification and detrimental memory impairment in AD. We propose ODC1 inhibition as a promising therapeutic strategy for AD to facilitate elimination of toxic molecules and prevent memory loss.

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