Alzheimer’s Mutations Disrupt Nerve-Muscle Links in Lab-Grown Tissue
Alzheimer's mutations disrupted nerve-to-muscle signals in a human cell chip with no brain, UCF researchers report. The work was done in lab models only.
Mutations that cause an inherited form of Alzheimer’s disease disrupted the connection between nerves and muscle in lab-grown human tissue that contained no brain or spinal cord, researchers at the University of Central Florida (UCF) report. The result suggests that some of the balance, walking and coordination problems seen in people with Alzheimer’s may start in nerves outside the brain.
The findings were published in Alzheimer’s & Dementia, the journal of the Alzheimer’s Association (DOI: 10.1002/alz.71281). The work was done in cell-based models, not in patients.
How the team built a body part without a brain
The group, led by James Hickman, a professor at UCF’s Nanoscience Technology Center, and research professor Xiufang “Nadine” Guo, worked with scientists at the healthcare technology company Hesperos. The National Institute on Aging, part of the National Institutes of Health, funded the study.
They used a “human-on-a-chip” system, a small laboratory device that brings several types of human cells together under controlled conditions. Hesperos, which Hickman co-founded, develops and manufactures these systems. According to UCF, such chips can reproduce interactions between different tissues, which a dish of one cell type cannot, and they offer an alternative to animal models that do not always reflect human disease.
For this study the team modeled a neuromuscular junction, the spot where a motor neuron signals a muscle cell to contract. The model had no brain and no spinal cord by design. The researchers paired healthy muscle cells with motor neurons grown from stem cells that carried mutations tied to familial Alzheimer’s, a rare inherited form that usually appears between ages 40 and 65, earlier than the more common form.
What the measurements showed
The scientists measured how reliably nerve signals produced muscle contractions and how long the muscle could keep contracting before it tired. The mutation-carrying motor neurons communicated poorly with the healthy muscle. Because nothing in the system came from the central nervous system, the team concludes that the mutations can damage this connection directly.
“You can’t move unless the motor circuit works,” Hickman said. He compared the measurements to a doctor tapping a knee to test a reflex, which checks the same nerve-to-muscle link.
Doctors have long noticed that some Alzheimer’s patients develop changes in balance, coordination and gait years before memory trouble becomes clear. One open question was whether those changes are only a result of brain damage or whether the disease also affects peripheral nerves, the nerves outside the brain and spinal cord. Hickman said this is the first demonstration that peripheral nervous system deficits can arise directly from the mutations.
What is still unknown
The authors state that the experiments do not show that these nerve changes necessarily happen before memory loss in patients. Whether the lab results match the course of the disease in people is untested, particularly for the more common forms of Alzheimer’s, which the study did not model. The work used cells carrying familial Alzheimer’s mutations, so it says nothing yet about people without those mutations.
The article does not describe any patient testing, and the researchers do not claim a diagnostic test or a treatment.
Why it matters
If later studies confirm that movement changes show up early in some patients, tests of walking, coordination or nerve-to-muscle activity could one day help flag disease-related changes before more obvious neurological symptoms. That remains a possibility the authors raise, not a result.
The finding also bears on drug design. “It means drugs that target the brain may not fix problems in the rest of the body,” Hickman said. Guo added that detecting motor changes and acting early could help delay the onset of central nervous system symptoms, and that regular physical activity is associated with better cognitive well-being.
The team also sees wider use for human-on-a-chip systems in studying other diseases and testing possible therapies, since they track how a treatment affects interactions between tissues. Hickman described the project as the result of three decades of work on more realistic laboratory models of disease.
Source: ScienceDaily
