Ghrelin is famously known as the “hunger hormone” for the role it plays in promoting appetite. The hormone is secreted by the gastrointestinal tract, has the ability to cross the blood-brain barrier, and ultimately, trigger brain cells in the hypothalamus to signal we are ready to eat. Recent research, however, has started to uncover other roles ghrelin may play, outside of the hypothalamus.
Ghrelin has been found to be active in the hippocampus leading some scientists to hypothesize it plays an important role in learning and memory. Prior research exploring whether activating ghrelin receptors in the hippocampus could slow the progression of Alzheimer’s have proven inconclusive, in both humans and animals. This new research suggests cognitive activity in a healthy hippocampus requires activity from both ghrelin receptors and dopamine receptors.
“Our hypothesis is that this dissociation between ghrelin and dopamine receptors may be what is affecting cognition in Alzheimer’s patients,” says corresponding author on the new research, Heng Du. “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.”
Du suggests this process is similar to the way insulin receptors malfunction in patients with type 2 diabetes. Regardless of how much insulin is present in the body, the fundamental mechanism is dysfunctional. So in the case of hippocampal deficits seen in Alzheimer’s disease, while ghrelin deficiency could be playing a role, simply administering extra ghrelin or trying to activate ghrelin receptors may not be an effective approach.
The new strategy outlined in a paper published in the journal Science Translational Medicine, suggests simultaneous activation of ghrelin and dopamine receptors in the hippocampus could be the solution. Testing the strategy, the researchers administered Alzheimer’s modeled mice with two compounds designed to trigger both kinds of receptors.
“When we gave these compounds simultaneously, we saw improved cognition and memory in the [Alzheimer's disease] mice, and lesions in the hippocampus were reduced,” says Du. “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.”
It’s still very early days for the research, and this study is essentially just a proof of concept affirming this particular neuronal mechanism can be effectively altered and improved. If validated by future work, however, this mechanism could be effectively targeted to slow, or even stop, some cognitive decline associated with not just Alzheimer’s disease, but aging on general.
“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,” says Du.
Another intriguing implication of the study is the suggestion Alzheimer’s may be a broader systemic disorder. If these cognitive symptoms can be associated with more general metabolic or hormonal pathways then there hypothetically could be a number of ways to inhibit its onset, without specifically trying to target parts of the brain where degeneration is identified.
The new research was published in the journal Science Translational Medicine.
