Could the Link Between “Hunger Hormone” and Alzheimer’s Explain Clinical Trial Failure?

Ghrelin is a "hunger hormone" that is mainly produced in the stomach but is also released in small amounts from the pancreas and the brain. It is named the "hunger hormone" due to its role in appetite stimulation – when administered to humans, ghrelin increases food intake by up to 30%. It exerts its effect on the hypothalamus, a region of the brain that is crucial for appetite control.

In a new study published in Science Translational Medicine, a team of researchers from the University of Texas Dallas have explored ghrelin's potential role in the neurodegenerative disorder, Alzheimer's disease (AD).

"This is a proof-of-concept study, but we are very encouraged by the results," says Heng Du, associate professor of biological sciences at UT Dallas and corresponding author of the study.

The "hunger hormone" and memory

The hippocampus is a brain region crucial to learning, memory and emotions. In AD, it is one of the first areas to exhibit cell death and damage due to the build up of amyloid beta protein fragments. In a healthy hippocampus, ghrelin binds to its receptor, GHSR1α. This mediates activation of the dopamine receptor D1 (DRD1). The modulation of DRD1 by GHSR1α is critical for hippocampal synapse function and synaptic reorganization via the noncanonical Gαq-Ca²⁺ signaling pathway that is central to memory formation.

The role of GHSR1α in hippocampal synaptic function has raised the question of whether receptor dysfunction may contribute to the hippocampal synaptic deficits observed in AD.

The University of Dallas researchers decided to address this question using autoptic AD brain samples and an AD animal model. "Our hypothesis is that this dissociation between ghrelin and dopamine receptors may be what is affecting cognition in Alzheimer's patients," Du said. "As the brain loses the function of ghrelin receptors due to amyloid beta, the body tries to compensate by increasing the production of ghrelin and the number of ghrelin receptors. But the amyloid prevents the receptors from functioning."

β-amyloid suppresses ghrelin receptor

The scientists found that β-amyloid (Aβ) suppresses the activation of GHSR1α, and in turn disrupts GHSR1α-mediated activation of DRD1 in the hippocampus of AD patient samples.

Du has suggested that the condition could be likened to insulin resistance in individuals that have type 2 diabetes: "To compensate, patients in the early stages of type 2 diabetes produce more insulin to bind insulin receptors," Du said. "But they become insulin-resistant. No matter how much insulin your body produces, the insulin receptors are unable to activate the downstream biochemical reactions needed to transport glucose from blood into cells." It is possible that AD may be linked to ghrelin resistance.

This may explain why a recent clinical trial of a compound known as MK0677 that activates ghrelin receptors in the brain failed to slow the progression of AD.

Du and colleagues next decided to simultaneously apply the selective GHSR1α agonist MK0677 with the selective DRD1 agonist SKF81297 in the AD mouse model. They found that this combination rescued GHSRr1α function from Aβ inhibition, mitigating hippocampal synaptic injury and improving spatial memory.

"When we gave these compounds simultaneously, we saw improved cognition and memory in the AD mice, and lesions in the hippocampus were reduced," Du said. "Activating both receptors at the same time was key; it restored the receptors' ability to form complexes. When this happens, we suspect the ghrelin receptor becomes protected and can no longer bind to amyloid beta."

More than just a brain disease

Du has filed a patent on this approach, saying: "More research is needed, but targeting this mechanism might prove therapeutically useful."

He places emphasis on viewing AD as more than just a "brain disorder" but rather a "systemic" disorder. "As we age, we tend to experience changes in metabolism. These affect the heart and the gastrointestinal system, but maybe they also are affecting the brain by altering the ghrelin receptor," he said. "We know that even in the absence of dementia, many older people have memory problems, and this could be related to the dissociation between the receptors in the brain, even without the presence of amyloid."

Reference: Tian et al. 2019. Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer′s disease. Science Translational Medicine. DOI: 10.1126/scitranslmed.aav6278.