Scientists at the UCL School of Pharmacy have developed a new human stem cell–based model that recreates key features of brain circuitry affected in Alzheimer’s disease, offering a powerful tool to study how the condition disrupts neural communication.
Alzheimer’s disease is associated with a breakdown in the balance between excitatory and inhibitory signals in the brain, but this has been difficult to measure directly in human neurons. The team of Prof Afia Ali, alongside colleagues at the Institute of Neurology, addressed this by generating a co-culture of human neurons and support cells derived from patient stem cells carrying a familial Alzheimer’s mutation, alongside matched healthy controls.
The model successfully integrates excitatory neurons, inhibitory interneurons, and astrocytes, and shows functional electrical activity. Notably, Alzheimer’s-derived cells displayed increased synaptic activity, thus providing evidence of network hyperexcitability, alongside structural changes in neurons.
“This is one of the first human models to capture Alzheimer’s-related dysfunction at the level of neural circuits,” said corresponding author, Prof Afia Ali. “By developing a novel neuronal microcircuit based on mutations relevant to Alzheimer’s patients, we can now directly examine how disease-causing mutations alter brain function and begin to test approaches to restore normal activity.”
This validated human neuron co-culture system enables precise study of Alzheimer’s disease in a physiologically relevant model, helping bridge the translational gap between animal studies and the human brain. It also supports analysis of normal control brain activity and healthy-disease comparisons, while also providing a valuable platform to investigate disease mechanisms and screen targeted therapies aimed at restoring normal brain activity.
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