Scientists link 'hunger hormone' to memory in Alzheimer's study

September 03, 2019

Scientists at The University of Texas at Dallas have found evidence suggesting that resistance to the "hunger hormone" ghrelin in the brain is linked to the cognitive impairments and memory loss associated with Alzheimer's disease (AD).

The findings, based on observations of postmortem brain-tissue samples from Alzheimer's patients and on experiments with a mouse model of AD, also suggest a possible treatment strategy for the incurable neurodegenerative disorder that affects about 5.8 million older adults in the United States.

The research was published Aug. 14 as the cover article in the journal Science Translational Medicine.

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

Produced in the stomach, ghrelin sends signals to the brain that regulate energy balance and body weight. Often called the hunger hormone, it plays a role in appetite and meal initiation. But ghrelin also has been implicated in learning and memory.

The hippocampus region of the brain -- crucial to learning, memory and emotions -- is one of the first to suffer cell death and damage in Alzheimer's disease due to a toxic buildup of protein fragments called amyloid beta.

In a healthy hippocampus, ghrelin binds with proteins called ghrelin receptors, which combine with similarly activated receptors for the neurotransmitter dopamine. The two receptors then form a protein complex that helps maintain communication between brain cells and, ultimately, memory.

In the new study, Du and his colleagues found that amyloid beta binds to ghrelin receptors in the hippocampus, blocking their ability to combine with dopamine receptors.

"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."

Du likened the condition to insulin resistance found in individuals with type 2 diabetes. In that disease, insulin receptors malfunction.

"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.

"Similarly, based on our findings, Alzheimer's might be linked to ghrelin resistance."

Du said the new findings help explain why a recent clinical trial of a compound called MK0677 -- designed to activate ghrelin receptors in the brain -- proved unable to slow the progression of Alzheimer's.

To test a different approach in their mouse model of AD, Du's team gave the mice MK0677 and another compound -- SKF81297 to activate dopamine receptors -- at the same time.

"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 research is needed, but targeting this mechanism might prove therapeutically useful."

Du, who has filed for a patent on the approach, said the team's findings suggest that Alzheimer's might be more than just a brain disease.

"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.

"I'm starting to think of Alzheimer's as a systemic disorder, and that we should pay more attention to the metabolic and hormonal path of the disease."
-end-
Other UT Dallas researchers involved in the study were co-lead authors Jing Tian, doctoral student in molecular and cell biology, and Dr. Lan Guo, research assistant professor of biological sciences; Dr. Sven Kroener, associate professor of behavioral and brain sciences, and his doctoral students Christopher Driskill and Aarron Phensy; Esha Gauba, doctoral student in molecular and cell biology; and visiting scholars Dr. Shaomei Sui and Dr. Qi Wang.

Additional authors include Dr. Jeffrey Zigman, professor of internal medicine at UT Southwestern Medical Center, and Dr. Russell Swerdlow, director of the University of Kansas Alzheimer's Disease Center and the University of Kansas Medical Center Neurodegenerative Disorders Program.

The research was funded by the National Institutes of Health and the Alzheimer's Association.

University of Texas at Dallas

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.