UCF Human-on-a-Chip Model Shows Familial Alzheimer’s Mutations Directly Disrupt Neuromuscular Junctions

The team used Hesperos human-on-a-chip platforms containing induced pluripotent stem cell-derived motor neurons and skeletal muscle from patients carrying APP or PSEN1 mutations. These compartmentalized cultures formed functional neuromuscular junctions that were monitored via electrophysiological recordings and calcium imaging over 28 days. Mutation-bearing motor neurons showed reduced synaptic vesicle release and 40% weaker contractile force compared with isogenic controls, establishing a peripheral mechanism independent of central nervous system pathology.

Prior observational studies have documented gait slowing and postural instability up to a decade before cognitive decline in both familial and sporadic Alzheimer’s cohorts. The present cell-system data supply a plausible cellular substrate for those prodromal motor changes and indicate that current brain-centric therapies may leave peripheral deficits unaddressed. Because the model isolates peripheral neurons, it also offers a scalable platform for testing compounds that stabilize neuromuscular transmission.

Next steps include longitudinal motor assessments in presymptomatic mutation carriers and integration of peripheral biomarkers into prevention trial endpoints. If replicated in larger patient-derived lines, the findings could support regulatory acceptance of gait or grip-strength measures as early efficacy signals, shortening trial durations and expanding therapeutic targets beyond the brain.