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

Astrocytes are a double-edged sword in Alzheimer’s

31 March 2023

Star-shaped brain cells known as astrocytes play both beneficial and harmful roles in Alzheimer’s disease.

A distinctive feature of Alzheimer’s disease is the formation of mats of misfolded proteins known as beta-amyloid plaques in the brain. But despite decades of research, the roles these plaques play in memory lost was unclear.

Now, a team led by researchers from the Institute for Basic Science in South Korea has found that astrocytes contribute to memory loss when they clear toxic ammonia derived from beta-amyloid plaques.

Astrocytes convert ammonia into less toxic urea, but to do this they switch to the same cycle used to detoxify ammonia as the liver uses. This produces harmful by-products such as ammonia, hydrogen peroxide and the neurotransmitter GABA, which leads to memory impairment.

Based on the finding, the team propose silencing the enzyme ornithine decarboxylase 1 (ODC1) as a promising strategy for removing toxic molecules while preventing memory loss.

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References

1. Cell Metabolism 34, 1104–1120 (2022). doi: 10.1016/j.cmet.2022.05.011