Targeted inhibition of an enzyme linked to the urea cycle called ornithine decarboxylase 1 (ODC1) in star-shaped cells in the brain called astrocytes, could prove beneficial in restoring memory functions in Alzheimer’s Disease (AD) patients, a preclinical study suggests.
The findings were published on June 22, 2022, in an article in the journal Cell Metabolism titled, “Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease.” The study was led by C. Justin Lee, PhD, director of the Center for Cognition and Sociality at the Institute for Basic Science (IBS) in South Korea and Hoon Ryu, PhD, a scientist at IBS.
Earlier studies by the same group had uncovered that hydrogen peroxide (H2O2) produced by severely reactive astrocytes is a key inducer of neurodegeneration in AD. This led them to further investigate the molecular underpinnings of the astrocytic response in AD, specifically the role of astrocytes in the conversion of amyloid-beta to urea in the brain.
The urea cycle is a major metabolic pathway in digestive and excretory processes. It converts ammonia, a toxic byproduct of protein digestion, into urea, in the liver. This urea is then excreted in urine. Earlier studies have reported increased brain urea in AD patients. This led Lee, Ryu and their team at IBS to wonder if the urea cycle played a role in AD pathology. Their experiments led them to conclude that the urea cycle is turned on in astrocytes in AD, to remove toxic amyloid-beta aggregates by converting them to urea.
However, this causes astrocytes to produce another toxic metabolite called ornithine. The astrocytes must produce ODC1 to convert ornithine to putrescine. Putrescine is the key precursor of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Therefore, the seemingly beneficial upregulation of the urea cycle in astrocytes results in the detrimental consequences of increased GABA and other toxic by products such as H2O2 and ammonia in the brain, through the putrescine pathway.
The ammonia generated reinforces the urea cycle in a positive feedback loop, triggering the generation of more toxic byproducts. Excessive GABA from astrocytes disrupts the balance of excitatory and inhibitory neurotransmission, resulting in memory loss. The current study builds on the team’s earlier findings to clarify mechanisms by which GABA, H2O2, and ammonia further increase neuronal cell death and loss of memory in AD.
First author, Yeon Ha Ju, PhD, a postdoctoral fellow in Lee’s lab, said, “For years, scientists have been debating about the beneficial and detrimental role of reactive astrocytes. With these findings our group clearly demarcates the beneficial urea cycle from the detrimental conversion of ornithine to putrescine and GABA, thereby providing evidence of the dual nature of astrocytes in the Alzheimer’s Disease brain.”
The new mechanistic insight led the team to explore the therapeutic potential of silencing ODC1 in astrocytes to cut down the generation of toxic byproducts in a transgenic mouse model of AD. They found the strategy reduced excessive GABA levels in the hippocampus and enabled the AD mouse model to recover from reactive astrogliosis and memory impairment. In addition, the mice had few amyloid-beta plaques upon ODC1 silencing.
Lee said, “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 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.”
As part of the study, the scientists conducted RNA sequencing to detect changes of gene expression levels in amyloid beta-treated astrocytes and in post-mortem brain samples of human AD patients. They measured ammonia and urea concentrations in vitro and developed a urea sensor to measure real-time urea concentrations in the mouse brain. They also silenced specific genes in culture and animal models to analyze the balance between the urea and putrescine pathways and conducted electrophysiogical and behavioral assays to ascertain brain function in the mouse model.
The study shows, the urea cycle is in overdrive in reactive astrocytes in the brain in AD in mouse models and human brain tissue from AD patients and suggests inhibiting putrescine production could have a beneficial effect in restoring memory loss in patients with AD.