The Astrocyte Urea Cycle in Alzheimer's Disease

Alzheimer's disease, like all neurodegenerative conditions, is a complex and still incompletely understood disease. Many pathological mechanisms are involved, and it is far from clear as to which of them are more or less relevant at different stages of the progression of Alzheimer's disease. This poor understanding is well illustrated by the ongoing failure of clinical trials targeting removal of amyloid-β. The materials here are an interesting discussion of a pathological role undertaken by astrocytes in response to amyloid-β; it remains to be seen as to whether further evidence will show that this provides a significant contribution to loss of function in patients.

Star-shaped supporting cells in the brain, called astrocytes, are greatly involved in Alzheimer's disease and its progression. After studying basic cellular pathways and how they change in astrocytes, the researchers have identified the conversion of amyloid-beta to urea in the brain as an important mechanism. The urea cycle is widely studied and understood as a major metabolic pathway in the liver and kidneys, as a part of our digestive and excretory processes. Surprisingly, previous studies have reported increased urea in the brain of Alzheimer's disease patients, which led researchers to wonder if the urea cycle played any role in the pathology of the disease. To their surprise, they found that the urea cycle is 'switched on' in the astrocytes of the Alzheimer's disease brain, in order to clean up the toxic amyloid-beta aggregates and remove them in the form of urea.

However, this isn't as beneficial as it sounds. The group found that the switching on of the urea cycle causes the production of ornithine, another metabolite that accumulates in the cell and needs to be cleaned up. The hardworking astrocytes produce the enzyme ornithine decarboxylase 1 (ODC1) in this condition to deal with the accumulated ornithine and convert it to putrescine. This consequently increases the levels of neurotransmitter γ-aminobutyric acid (GABA), as well as toxic byproducts like hydrogen peroxide (H2O2) and ammonia in the brain. This ammonia further feeds back into the urea cycle and continues this process, causing more and more accumulation of toxic byproducts. High levels of GABA released by these astrocytes play an inhibitory action on neuronal transmission, contributing to the tell-tale loss of memory in Alzheimer's disease.

"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."


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