Urine may explain why Alzheimer’s disease causes memory loss

DAEJEON, South Korea — What does urinating have to do with Alzheimer’s disease? A new study finds the process which creates our pee may also be to blame for exacerbating memory loss in dementia patients.

Researchers in South Korea have discovered a link between the body’s urea cycle and a group of cells which clean up harmful plaques in the brain. Until now, scientists believed that misfolded amyloid-beta protein clumped together to form blockages in the brain — leading to the onset of Alzheimer’s and eventual cell death. However, there has always been a missing link between the formation of harmful plaques and Alzheimer’s symptoms, such as memory loss.

A team from the Institute for Basic Science (IBS) has finally found the answer. The new work builds on their 2020 study that found astrocytes play a major role in Alzheimer’s disease and its progression. These star-shaped cells in the brain regulate blood flow, transfer mitochondria to neurons, and supply the building blocks of neurotransmitters. However, they also clear debris, which is ironically part of the problem.

Scientists discover the missing link in Alzheimer’s onset

While examining changes in the cellular pathways of the astrocytes, the IBS team found the missing link they were looking for — the conversion of amyloid-beta protein to urea inside the brain.

Throughout the body, the urea cycle is an important process which turns toxic byproducts (like ammonia) into nontoxic waste (urea). While the body can’t excrete toxic substances like ammonia, which form during protein digestion, it can convert it to urea and expel it through the kidneys in the form of urine.

In Alzheimer’s patients, scientists have previously discovered higher urea levels in their brains. With that in mind, the South Korean team wondered if this same urea cycle was contributing to dementia onset.

Their study finds the urea cycle is indeed “switched on” in the astrocytes of Alzheimer’s-diseased brains. Study authors say the cells are trying to clean out the toxic amyloid-beta aggregates and convert them into urea. While that may be a good plan, the team found that switching on the urea cycle in these particular cells actually starts a vicious cycle that causes more memory loss!

Breaking down the vicious cycle between urea and dementia

Researchers explain that turning on the urea cycle in brain cells results in the production of ornithine, another metabolite which builds up in the brain and needs to be cleaned out. The astrocytes keep working by producing the enzyme ornithine decarboxylase 1 (ODC1) in order to clean up the ornithine. This process converts ornithine into putrescine.

However, all of that increases the levels of the neurotransmitter γ-aminobutyric acid (GABA), and toxic byproducts such as hydrogen peroxide (H2O2) and ammonia throughout the brain.

The creation of ammonia in the brain keeps the urea cycle going, as it tries to deal with the new toxins and convert them into urea as well. Unfortunately, this just continues to create more and more toxic substances for the astrocytes to deal with, in a never-ending cycle.

Brain cycle
Next-Generation RNA Sequencing and metabolite analysis reveals that the non-cyclic urea metabolism of astrocytes turns to a cyclic state in reactive AD-like conditions. (Institute for Basic Science)

In the end, the high levels of GABA created by the astrocytes inhibit neuronal transmission in the brain — resulting in the classic symptom of memory loss in Alzheimer’s patients.

“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,” says first author Ju Yeon Ha in a media release.

Switching off the brain’s urea cycle may cure Alzheimer’s

With this new knowledge, the team experimented on a group of mice with Alzheimer’s — silencing the gene that produces ornithine decarboxylase 1 in astrocytes. Researchers found that this stopped the excessive GABA production and neuronal inhibition in the hippocampus — the brain region controlling memory and learning.

The mice performed better in memory-related tests and also completely recovered from Alzheimer’s-related memory loss after the ODC1 knockdown. The team even found significantly fewer amyloid-beta plaques in mice with a silenced ODC1 gene.

“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. 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,” concludes corresponding author C. Justin Lee.

The study is published in the journal Cell Metabolism.

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