Higher levels of unacylated-ghrelin, the most prevalent form of ghrelin (acyl-ghrelin) — a gut hormone with neuroprotective properties — suppress nerve cell growth in the hippocampus to affect spatial memory, according to a study in mice.
Importantly, the study team also found unacylated-ghrelin levels to be higher-than-normal in people with Parkinson’s disease dementia (PDD).
These findings highlight a previously unknown damaging effect of unacylated-ghrelin in the hippocampus (a brain region involved in learning and memory), suggesting a potential link between this form of the hormone and dementia in Parkinson’s patients.
“Our work highlights the crucial role of ghrelin as a regulator of new nerve cells in the adult brain, and the damaging effect of the UAG [unacylated-ghrelin] form specifically,” Jeff Davies, PhD, an associate professor at Swansea University Medical School, and the study’s senior author, said in a press release.
Unacylated-ghrelin “represents an important target for new drug research, which could lead ultimately to better treatment for people with Parkinson’s,” Davies added. Study data also suggested the ratio between acyl and unacylated forms of ghrelin “could also serve as a biomarker, allowing earlier identification of dementia” in these patients.
The study, “Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans,” was published in the journal Cell Reports Medicine.
There is a close relationship between cognitive performance and nutritional status, but its underlying mechanisms remain poorly understood. Several studies point to acyl-ghrelin, commonly known as ghrelin, a hormone released by the gut during food restriction, as one of the contributors to this link.
Acyl-ghrelin was found to promote nerve cell growth (or neurogenesis) in the adult hippocampus, a process essential for spatial memory, which is impaired in Parkinson’s disease and dementia, but rises with exercise and calorie restriction. (Spatial memory is often defined as “retain and recall,” a form of memory that makes possible an understanding of environment — like navigating a home town — and remembering where things are.)
Previous studies in a mouse model of Parkinson’s showed that calorie restrictions increase acyl-ghrelin blood levels, which in turn promote the survival of dopaminergic neurons — the nerve cells that are progressively lost in Parkinson’s — and prevent the development of disease symptoms.
The most well-known form of the hormone, acyl-ghrelin, is the result of a chemical modification in ghrelin’s most abundant form, unacylated-ghrelin, by the enzyme ghrelin O-acyl-transferase (GOAT).
While unacylated-ghrelin was initially considered an inactive precursor of acyl-ghrelin, increasing evidence suggests that it works as a hormone with distinct, and in some cases opposite, effects to acyl-ghrelin. Its role in the hippocampus, however, is largely unknown.
Researchers at the U.K. medical school and colleagues discovered that unacylated-ghrelin has opposite effects to acyl-ghrelin in the hippocampus, and on the spatial memory of mice. They also showed that levels of these ghrelin forms are altered in people with Parkinson’s dementia.
They began by increasing the levels of unacylated-ghrelin in adult mice, either by administering the hormone directly into the bloodstream or by genetically deleting GOAT, and found hippocampal neurogenesis and neuroplasticity — a neurologic process essential for learning — were significantly reduced.
High levels of unacylated-ghrelin also impaired the animals’ spatial memory, which could be restored by treating mice daily with a seven-day course of acyl-ghrelin.
Further experiments using mouse hippocampal cells grown in the lab showed that acyl-ghrelin promoted nerve cell growth and survival in a brain-derived neurotrophic factor (BDNF)-dependent manner, and that unacylated-ghrelin could reverse these effects.
BDNF is a signaling molecule known to prevent the loss of dopaminergic neurons, and whose mutations have been associated with an increased risk of Parkinson’s disease-related cognitive impairment.
“These findings suggest that [GOAT-mediated chemical modification] of ghrelin is important to neurogenesis and memory in mice,” the researchers wrote.
To assess its potential relevance in people, the team analyzed the levels of both forms of ghrelin in Parkinson’s patients with or without dementia, as well as in age-matched healthy individuals serving as controls.
Results showed that PDD patients had a significantly lower ratio of acyl:unacylated forms of ghrelin in the blood (higher levels of unacylated relative to acyl ghrelin levels), compared with Parkinson’s patients without cognitive impairment and healthy people.
In agreement, cognitive impairment was found to be associated with a reduced ratio between the two forms, suggesting it “may be valuable as a diagnostic biomarker for human dementia.” The researchers noted, however, that larger studies are needed to confirm if changes in this ratio are specific to PDD or a biomarker of dementia in general.
Interestingly, while both groups of Parkinson’s patients had significantly lower levels of GOAT in the hippocampus, only those with dementia were found to have a significantly lower number of hippocampal cells producing GOAT.
“We describe how a [chemical] modification to a circulating factor modulates, in either direction, neurogenesis and cognition in mice,” the researchers wrote, adding that manipulating such modification “may offer therapeutic opportunities to ameliorate cognitive decline in human neurodegenerative disease.”
Further studies are needed to determine whether these ratio changes in ghrelin forms are specific to Parkinson’s dementia.
“Nonetheless, we provide a possible mechanistic link between circulating ghrelin, hippocampal function, and PDD in humans,” the team concluded.
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