On 14 August, Dr Jing Tian and colleagues published a paper in Science Translational Medicine, showing that Ghrelin receptor interacts with dopamine receptors during the development of hippocampal lesions in Alzheimer’s disease (AD).
The hippocampus is one of the earliest brain structures to be affected in the development of AD: connections between synapses are progressively lost, causing cognitive deficits. Although Ghrelin, known as the “hunger hormone”, is produced in the stomach, its receptors are present at high levels in the hippocampus. Intriguingly, researchers have recently shown that Ghrelin receptors can directly interact with receptors for dopamine, a neurotransmitter that is dysregulated in AD. This suggests that Ghrelin may have a physiological function in the brain - however studies have yet to determine what its role may be during the development of AD.
To answer this question, Dr Tian and colleagues studied brain samples donated by people with AD and performed experiments using mouse models of AD. In both models they observed a direct interaction between amyloid beta (Aβ) and the Ghrelin receptor (GHSR1α). This interaction caused the Ghrelin receptor to be dysfunctional, in turn preventing it from linking with the DRD1 dopamine receptor. To see whether losing this link had a functional effect, researchers studied mice in which the GHSR1α receptor has been genetically removed. They observed that these mice had similar hippocampal lesions and memory deficits to AD mice. Interestingly, treatment of AD mice with two drugs that selectively stimulate the Ghrelin and DRD1 receptors reduced AD symptoms in these animals. However, treatment with each drug in isolation did not have the same beneficial effect, suggesting that activating both receptors at the same time is key. Based on these findings, the researchers suggested that combination therapy with drugs that stimulate the Ghrelin and dopamine receptors may have therapeutic benefits.
