Scientists at the University of Central Florida (UCF) have discovered that genetic mutations associated with Alzheimer’s can interfere with the nerves that control muscle movement, even without involvement from the brain or spinal cord. The findings could help explain why some people with Alzheimer’s experience changes in walking, balance, or coordination long before noticeable memory problems emerge.

The discovery raises the possibility that movement difficulties could provide earlier warning signs of the disease and that treatments focused exclusively on the brain may overlook important problems elsewhere in the body.

The research was led by James Hickman, a professor at UCF’s Nanoscience Technology Center, and Research Professor Xiufang “Nadine” Guo, working alongside scientists at the healthcare technology company Hesperos. Funded by the National Institutes of Health’s National Institute on Aging, the study used laboratory systems built from human cells to investigate how inherited Alzheimer’s mutations affect movement. The findings were published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“Motor deficits may be an earlier indication [of Alzheimer’s],” Guo says. “If we can detect those changes and intervene earlier, that could help delay the onset of central nervous system symptoms.”

Why Alzheimer’s Symptoms May Appear Before Memory Loss

Alzheimer’s is generally associated with progressive memory loss, confusion, and declining cognitive abilities. However, doctors have also observed that some patients develop physical symptoms, including changes in balance, coordination, and gait (manner of walking), years before clear cognitive difficulties become apparent.

These observations have raised an important question: Are such movement problems simply a consequence of damage occurring in the brain, or could Alzheimer’s also interfere directly with nerves elsewhere in the body?

To investigate, the UCF team focused on familial Alzheimer’s, a rare inherited form of the disease that typically develops earlier in life (from 40 to 65 years of age) than the more common form.

Their experiments revealed that motor neurons carrying mutations linked to familial Alzheimer’s could disrupt the connections responsible for controlling muscles, even when the brain and spinal cord were completely absent from the experimental system.

Motor neurons are specialized nerve cells that transmit signals to muscles, telling them when to contract and produce movement. The new findings suggest that Alzheimer’s mutations can interfere with this process directly, rather than affecting movement only through damage to the brain.

“This is the first time it’s been demonstrated that deficits in the peripheral nervous system can arise directly from these mutations,” Hickman says. “It means drugs that target the brain may not fix problems in the rest of the body.”

The peripheral nervous system includes the nerves located outside the brain and spinal cord. These nerves carry signals between the central nervous system and the rest of the body, helping control movement, sensation, and other essential functions.

Guo also points out that preserving the ability to move could have benefits beyond physical health. Regular physical activity is associated with better cognitive well-being, so protecting motor function may also help support brain health.

How a Miniature Human Cell System Revealed the Discovery

To examine the relationship between Alzheimer’s mutations and muscle movement, the scientists used an innovative laboratory platform known as “human-on-a-chip” technology.

Developed and manufactured through Hesperos, a company co-founded by Hickman, these miniature systems bring different types of human cells together under controlled conditions. They allow researchers to recreate specific biological functions and observe how diseases interfere with them.

Unlike conventional laboratory experiments that examine isolated cells, these systems can reproduce important interactions between different tissues. They also provide an alternative to animal models, which do not always accurately reflect how human diseases behave.

For this study, the team created a miniature model of the neuromuscular junction, the connection where a motor neuron communicates with a muscle cell.

The model was deliberately designed without a brain or spinal cord. This was a crucial part of the experiment because it allowed the researchers to investigate whether Alzheimer’s-related changes could cause movement problems independently of the central nervous system.

The scientists combined healthy muscle cells with motor neurons derived from stem cells that carried genetic mutations associated with familial Alzheimer’s disease. Stem cells are cells that can develop into specialized types of cells, making them valuable tools for studying human diseases in the laboratory.

The researchers then examined how effectively the altered nerve cells communicated with otherwise healthy muscle tissue.

The results showed that the Alzheimer’s-associated mutations could interfere with normal nerve-to-muscle function. This suggests that at least some movement difficulties linked to the disease may arise directly in the peripheral nervous system rather than being caused entirely by degeneration in the brain.

Why Damaged Nerve Connections Can Affect Walking and Balance

Every voluntary movement depends on successful communication between the nervous system and the muscles.

At the neuromuscular junction, an electrical signal traveling along a motor neuron triggers chemical communication that causes a muscle to contract. This process makes everyday activities possible, from walking and maintaining posture to lifting objects and performing precise movements.

When the connection becomes impaired, muscles may respond less effectively to nerve signals. Depending on the severity and location of the problem, this can contribute to weakness, reduced coordination, and difficulty sustaining physical activity.

To evaluate these effects, the research team measured how consistently nerve signals produced muscle contractions and how long the muscles could continue contracting before becoming fatigued.

These measurements provided a direct assessment of how well the nerve and muscle cells worked together. They also resemble aspects of the functional testing physicians use when examining patients with movement disorders.

“You can’t move unless the motor circuit works,” Hickman says. “When a doctor taps your knee to check your reflex, they’re testing that exact connection.”

By demonstrating impaired nerve-to-muscle communication in a system containing no brain or spinal cord, the study provides evidence that mutations linked to familial Alzheimer’s can produce effects beyond the central nervous system.

However, the experiments do not establish that these changes necessarily occur before memory loss in patients. Further research will be needed to determine how closely the laboratory findings reflect the progression of Alzheimer’s in people, particularly those with the more common forms of the disease.

Could This Discovery Lead to Earlier Alzheimer’s Detection?

The findings suggest a potentially important new direction for Alzheimer’s research: looking beyond memory and other cognitive symptoms when investigating the disease.

If future studies confirm that changes in motor function are detectable early in certain patients, tests of walking, coordination, or nerve-to-muscle activity might eventually help identify disease-related changes before more obvious neurological symptoms develop.

The results also raise questions about treatment. Many Alzheimer’s therapies are designed to address processes occurring in the brain, but medications that target the central nervous system may not necessarily correct abnormalities affecting peripheral nerves and muscles.

Understanding these separate effects could help researchers investigate treatments that protect physical function alongside cognitive health.

Human-on-a-Chip Technology Could Transform Disease Research

Beyond the implications for Alzheimer’s, the researchers see considerable potential in using human-on-a-chip systems to investigate other diseases and evaluate possible treatments.

Because these platforms contain human cells and reproduce measurable biological activities, they can help scientists observe disease-related changes in conditions that more closely resemble human physiology than some conventional experimental models.

This approach may be particularly useful in drug development, where researchers need to understand not only how a potential treatment affects individual cells but also how it influences interactions between different tissues.

Such systems can also uncover biological effects that may be difficult to detect in animal experiments, potentially helping researchers identify promising therapies and recognize limitations earlier in development.

For Hickman, the progress represents the culmination of three decades of work devoted to understanding disease through more realistic laboratory models.

“These systems let us study disease in a way that’s closer to what actually happens in the human body, and that’s what we need to develop better treatments,” he says.

Scientists at UC San Francisco may have uncovered an important part of the answer. Their research reveals a little-understood dopamine pathway linking the digestive system and the brain, helping explain how we develop a liking for certain flavors through repeated experience.

Dopamine is a chemical messenger involved in motivation, reward, and learning. Researchers have long known that it helps the brain recognize experiences worth repeating. However, most studies have examined rapid dopamine signals that appear within seconds of encountering something rewarding, such as the sight of a favorite meal.

The new research, published November 4 in Nature, examines a different system. This slower pathway responds to information coming from inside the body, allowing the brain to learn about the benefits of food after it has been consumed.

“We’ve shown that this slow dopamine system is what drives us to learn to like certain foods over time, and we can see where and how that happens,” said Zachary Knight, PhD, professor of Physiology and senior author of the study.

The findings offer a possible explanation for why an initially unpleasant flavor can gradually become enjoyable. Once the brain connects the taste of coffee with caffeine’s stimulating effects, Knight explained, “that coffee starts to taste a lot better.”

How the Gut Sends Reward Signals to the Brain

Scientists have spent decades investigating dopamine and its influence on behavior. Its familiar, rapidly acting signals help us respond to opportunities for reward. But dopamine also operates on a slower timescale, through a system that has received far less attention.

According to Knight, this slower process largely unfolds outside our conscious awareness.

When food enters the digestive tract, specialized sensors detect nutrients, including sugar and fat. Information about those nutrients travels toward the brain, where it can produce a dopamine response that develops gradually and continues for several minutes.

To investigate this process, Knight worked with James Grove, PhD, who was a graduate student at the time. They introduced nutrients directly into the stomachs of mice while monitoring dopamine activity throughout their brains.

The researchers used either sugar water or a liquid resembling a milkshake. Delivering these substances directly into the stomach allowed them to separate the effects of nutrients from the experience of tasting food.

The results revealed a powerful, prolonged dopamine response in a specific brain region called the anterior basolateral amygdala, or BLA.

The amygdala is involved in emotional processing and learning, including forming associations between experiences and their consequences. Scientists already knew that dopamine was released in this particular region, but its purpose had remained unclear.

“We could see that this dopamine is part of a different system and begin to understand its role,” he said.

Scientists Find a Brain Circuit That Changes Food Preferences

Finding the dopamine signal was only the beginning. The researchers next wanted to determine whether it actually influenced how animals learned to prefer different flavors.

They first interrupted the newly identified pathway in mice. The animals continued eating normally, indicating that the disruption did not prevent them from consuming food. However, they lost the ability to learn that an unfamiliar flavor was associated with receiving calories.

The team then conducted the opposite experiment.

After mice tasted a flavor containing no calories, the researchers artificially activated dopamine fibers in the BLA. Remarkably, the animals developed a preference for that flavor even though it provided no nutritional reward.

In effect, stimulating the pathway reproduced the learning signal that nutrients would ordinarily generate.

Together, the experiments showed that this dopamine system plays a critical role in teaching the brain which flavors predict rewarding nutritional effects.

A Surprising Discovery in the Left Side of the Brain

The researchers also looked for evidence that a comparable process occurs in humans. Brain imaging studies conducted by Knight’s collaborators revealed a strikingly similar pattern.

Dana Small, PhD, a psychologist at Yale University, revisited data from an earlier positron emission tomography (PET) study involving 13 men. Participants had consumed either a milkshake or a drink without calories.

Her analysis found that dopamine release following nutrient delivery was especially concentrated in the left side of the BLA.

A separate study led by Marc Tittgemeyer, PhD, and his colleagues provided additional evidence. Using functional magnetic resonance imaging (fMRI), which measures changes in brain activity associated with blood flow, the researchers examined 38 adults after they consumed glucose, a simple sugar.

They observed increased activity in the same brain region.

One of the most unexpected findings was that the response was not evenly distributed between the brain’s two hemispheres.

In both mice and humans, nutrients produced a considerably stronger dopamine response in the left BLA than in the corresponding region on the right.

That imbalance surprised Knight because brain networks responsible for essential functions, such as feeding, are generally expected to work in a relatively symmetrical fashion.

Why the left side plays such a prominent role remains unanswered. Knight’s laboratory is now investigating what causes this unusual difference.

Could This Discovery Help Scientists Change Food Cravings?

Identifying the pathway provides researchers with a clearer picture of how the digestive system influences the brain’s learned responses to food. It also raises an intriguing possibility: Could scientists eventually use this knowledge to change which foods people find appealing?

One area of interest involves GLP-1 medications, a class of drugs that mimic a hormone naturally released by the gut. These medications can substantially alter appetite and eating behavior.

Knight’s team did not investigate GLP-1 drugs in the new study, so it remains unknown whether they influence the dopamine pathway the researchers identified.

Still, Knight suggests that one possible explanation for some of their effects could involve reducing the dopamine signals generated when nutrients reach the digestive system. If that happens, foods might gradually become less rewarding because the brain would receive weaker signals reinforcing their flavors.

For now, this remains a hypothesis rather than a demonstrated effect of the medications.

The broader implications extend beyond hunger and fullness. Many approaches to changing eating behavior focus on reducing appetite or increasing feelings of satisfaction after a meal. The newly mapped pathway suggests that the brain’s process of learning food preferences could eventually become another target.

By influencing how the brain connects flavors with their consequences, future treatments might someday help people develop different preferences rather than simply making them feel less hungry.

“By understanding the steps between nutrient detection in the gut and learning in the brain, it might be possible to fine-tune them to subtly change our preferences for different foods,” Knight said.

The discovery offers a new perspective on why our tastes can change over time. From learning to enjoy bitter coffee to developing a preference for calorie-rich foods, what we love to eat may depend partly on a quiet conversation between the gut and brain that continues long after the first bite.

The research was supported by the National Institutes of Health (grants R01-DK106399, R01-DK138127, R01-NS116626, and R01-DK145100 and F31-NS120468).

The findings, published October 27 in the Journal of Experimental Medicine (JEM), reveal an unexpected connection between cholesterol production and the immune system. By interfering with this process, pantethine may help reduce the excessive immune activity responsible for psoriasis and potentially other autoimmune diseases.

How Overactive Immune Cells Contribute to Psoriasis

At the center of the discovery are dendritic cells, specialized immune cells that help organize the body’s defenses. These cells act as coordinators, identifying potential threats and directing other immune cells to respond.

Dendritic cells perform this role by capturing foreign substances called antigens and presenting them to T cells, which are immune cells that recognize specific threats. They also release chemical signals that recruit additional immune cells and trigger inflammation.

Although these activities are essential for fighting infections, problems can arise when dendritic cells become excessively active. Instead of helping protect the body, they can contribute to persistent inflammation and autoimmune diseases such as psoriasis.

“Emerging evidence highlights that metabolic pathways and their associated metabolites play vital roles in regulating immune cell function and autoimmune progression,” says Wei-Na Zhang, a researcher at the State Key Laboratory of Biomedical Analysis in Beijing. “But therapeutic strategies targeting metabolism in inflammatory diseases remain underexplored.”

Zhang led the research alongside Qing Xia, Ai-Ling Li, and Tao Zhou, also from the State Key Laboratory of Biomedical Analysis, and Cheng-Xin Li from The First Medical Center of Chinese PLA General Hospital in Beijing.

Scientists Discover a Hidden Link Between Cholesterol and Psoriasis

The researchers identified unusually high levels of enzymes called Vanins in dendritic cells from people with psoriasis and several other autoimmune diseases. These enzymes help regulate the processing of certain substances involved in cellular metabolism.

When the scientists reduced Vanin levels, dendritic cells became less active and were less capable of stimulating T cells. They also found that a drug designed to inhibit Vanins prevented psoriasis from developing in mice.

Further investigation revealed why these enzymes might play such an important role.

Vanins convert pantethine into vitamin B5, an essential nutrient that cells need to produce energy. Pantethine is already sold as a nutritional supplement and is commonly used to help lower blood cholesterol because it can reduce cholesterol production.

This connection is particularly interesting because cholesterol does more than circulate in the bloodstream. It also influences how immune cells function. Previous research has shown that cholesterol can stimulate dendritic cell activity, while elevated blood cholesterol is a major risk factor for developing psoriasis.

The team discovered that excessive Vanin activity reduces the amount of pantethine available inside dendritic cells. As pantethine levels fall, cholesterol production increases, causing these immune cells to become unusually active.

Restoring pantethine levels interrupted this process. The supplement reduced cholesterol accumulation within dendritic cells and helped suppress the excessive immune activation associated with inflammation.

“We found that pantethine administration effectively alleviated psoriasis in mice, suggesting that insufficient pantethine levels may be the crucial contributor to hyperactivation of dendritic cells and autoimmune inflammation following the up-regulation of Vanins,” Zhang says.

Common Supplement Shows Promise in Human Psoriasis Trial

Encouraged by the laboratory and animal findings, the researchers investigated whether pantethine might also benefit people living with psoriasis.

They conducted a small clinical trial involving 24 patients with the condition. All participants received a topical ointment containing calcipotriene/betamethasone, a combination treatment used to control psoriasis symptoms. Calcipotriene is a vitamin D derivative that helps regulate skin cell growth, while betamethasone is a corticosteroid that reduces inflammation.

Half of the participants also took pantethine tablets, allowing researchers to examine whether adding the supplement improved the results of standard treatment.

After 12 weeks, the patients who received pantethine alongside their prescribed ointment showed greater improvement in psoriasis symptoms. The benefits were especially noticeable among participants who had high blood cholesterol levels before treatment.

These findings suggest that pantethine could potentially serve as an additional treatment for psoriasis, particularly in patients whose cholesterol metabolism may be contributing to inflammation.

However, the trial included only 24 people, and the researchers emphasize that larger studies are necessary to confirm the supplement’s effectiveness. The human results also do not establish that the same biological mechanism observed in laboratory experiments is responsible for the improvement in patients.

“Our investigator-initiated clinical trial demonstrated encouraging therapeutic efficacy of pantethine as an adjunctive therapy in psoriasis, but these findings should be interpreted as proof-of-concept for clinical feasibility rather than direct mechanistic validation,” Zhang says. “Overall, our study uncovers the Vanin-pantethine-cholestrol axis as a key metabolic pathway governing dendritic cell activation and provides a foundation for therapeutic strategies targeting several dendritic cell-mediated autoimmune diseases.”

The protein, known as Miro1, was found at higher levels in the skeletal muscles of people with Type 2 diabetes. In preclinical experiments, scientists discovered that removing Miro1 restored the muscles’ response to insulin. They also found that exercise lowered Miro1 levels in people with the disease, offering new insight into how physical activity improves insulin sensitivity.

The findings were published in Nature Communications and could help researchers better understand the biological processes behind insulin resistance, a central feature of Type 2 diabetes.

How a Hidden Muscle Protein Affects Insulin Resistance

Miro1 (Mitochondrial Rho GTPase1) is located on the outer membrane of mitochondria, the tiny structures inside cells responsible for producing energy. Researchers believe that excessive amounts of this protein may interfere with how muscles respond to insulin, making it more difficult for the body to regulate blood sugar effectively.

To investigate this connection, the research team studied Miro1 in laboratory cells, preclinical models, and people living with Type 2 diabetes. By examining the protein across these different settings, they were able to explore its effects on muscle function and determine whether the findings could be relevant to human disease.

The results showed that Miro1 buildup impaired the muscles’ response to insulin. When researchers removed the protein in preclinical models, insulin responsiveness returned, providing evidence that Miro1 contributes directly to this process.

Exercise Reduces a Protein Linked to Type 2 Diabetes

The researchers also investigated whether exercise could influence Miro1 levels in people with diabetes. In a randomized controlled trial involving participants with obesity and Type 2 diabetes, they compared the effects of aerobic exercise with those of standard medical care.

People assigned to the exercise group experienced a decline in Miro1 levels in their muscles. These changes occurred alongside improvements in insulin sensitivity and the muscles’ capacity to produce energy.

The findings suggest that reducing Miro1 may be one of the ways exercise helps the body respond more effectively to insulin. They also raise the possibility that treatments designed to target the protein could eventually provide additional benefits alongside physical activity.

“Insulin resistance in muscle is at the heart of Type 2 diabetes, and its molecular causes have remained frustratingly unclear. This study, the product of years of work, identifies Miro1 as a key part of the answer. By tracing Miro1 from cells to preclinical models to patients, we show that Miro1 accumulation impairs the muscle’s response to insulin, that removing it causally restores that response in our models, and that exercise reverses its buildup in people. For the field, this is a new therapeutic target. For patients, it deepens our understanding of why exercise is so effective and opens a path toward treatments that could one day complement it,” said Dr. John P. Kirwan, the study’s senior author.

A Promising New Direction for Diabetes Treatment

Kirwan recently became executive director of the OU Health Harold Hamm Diabetes Center at the University of Oklahoma. He carried out the research while working at LSU’s Pennington Biomedical Research Center and has since brought his internationally recognized translational research program to the University of Oklahoma.

He also serves as Vice Provost for Diabetes Programs at the university and holds the Chickasaw Nation Endowed Chair in Diabetes Research.

The study’s first author, Elizabeth Heintz, is a doctoral candidate who worked in the Integrated Physiology and Molecular Medicine Laboratory at Pennington Biomedical. Christopher Axelrod, the study’s co-corresponding author, has also moved to the Harold Hamm Diabetes Center, joining Kirwan in continuing this line of research.

Dr. Jennifer Rood, Interim Senior Vice Chancellor and Executive Director of Pennington Biomedical, emphasized the importance of connecting laboratory discoveries with research involving patients and broader populations.

“This research exemplifies the breadth of scientific discovery at Pennington Biomedical, where research spans all levels, from basic science that reveals the biological mechanisms underlying disease to clinical studies and population-based research that informs public health,” said Dr. Jennifer Rood, Interim Senior Vice Chancellor and Executive Director of Pennington Biomedical. “Dr. Kirwan and his team’s findings on Miro1 demonstrate the value of this integrated approach, connecting fundamental discoveries about muscle function with insights into insulin resistance and the benefits of exercise in people with Type 2 diabetes. This work is advancing our understanding of diabetes and helping lay the foundation for future approaches to prevention and treatment.”

Could Targeting Miro1 Lead to New Diabetes Therapies?

Although the results are encouraging, scientists still need to establish whether directly targeting Miro1 can produce safe and effective treatments for people with Type 2 diabetes. The restoration of insulin responsiveness was demonstrated in preclinical models, while the human trial showed that exercise reduced Miro1 levels alongside improvements in insulin sensitivity.

Kirwan plans to continue investigating these findings at the Harold Hamm Diabetes Center. His research will combine laboratory experiments with studies involving people to uncover more of the biological mechanisms responsible for diabetes and explore new strategies for preventing and treating the condition.

“Type 2 diabetes is an affliction in Oklahoma and nationally,” he said. “Ultimately, we are looking for cures, and we hope these recent findings could be part of the solution.”

The study received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Center for Complementary and Integrative Health, the National Heart, Lung, and Blood Institute, and the National Institute of General Medical Sciences.