Researchers say they have shown the therapeutic benefits of genetically improving inhibitory interneurons and transplanting them into the brain of a mouse model of Alzheimer's disease. They published their study (“Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease“) in Neuron.
“Inhibitory interneurons regulate the oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in Alzheimer’s disease (AD). Network dysrhythmias in AD and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons,” write the investigators.
“We show that Nav1.1-overexpressing, but not wild-type, interneuron transplants derived from the embryonic medial ganglionic eminence (MGE) enhance behavior-dependent gamma oscillatory activity, reduce network hypersynchrony, and improve cognitive functions in human amyloid precursor protein (hAPP)-transgenic mice, which simulate key aspects of AD. Increased Nav1.1 levels accelerated action potential kinetics of transplanted fast-spiking and non-fast-spiking interneurons. Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice. We conclude that the efficacy of interneuron transplantation and the function of transplanted cells in an AD-relevant context depend on their Nav1.1 levels. Disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.”
Jorge Palop, Ph.D., an assistant investigator at the Gladstone Institutes, previously demonstrated that, in mouse models of Alzheimer's, the inhibitory interneurons do not work properly. So, the rhythms that organize the excitatory cells are disturbed and fail to function harmoniously, causing an imbalance in brain networks. This, in turn, affects memory formation and can lead to epileptic activity, which is often observed in patients with Alzheimer's disease.
Dr. Palop’s team found a way to reengineer inhibitory interneurons to improve their function. They showed that these enhanced interneurons, when transplanted into the abnormal brain of Alzheimer mice, can properly control the activity of excitatory cells and restore brain rhythms.
“We took advantage of the fact that transplanted interneurons can integrate remarkably well into new brain tissues, and that each interneuron can control thousands of excitatory neurons,” said Dr. Palop, who is also an assistant professor of neurology at the University of California, San Francisco. “These properties make interneurons a promising therapeutic target for cognitive disorders associated with brain rhythm abnormalities and epileptic activity.”
The researchers initially had to overcome a key challenge. When they transplanted regular interneurons, they saw no beneficial effects, presumably because Alzheimer's disease creates a toxic environment in the brain.
The scientists then genetically boosted the activity of inhibitory interneurons by adding the Nav1.1 protein. They discovered that the interneurons with enhanced function were able to overcome the toxic disease environment and restore brain function.
“These optimized neurons are like master conductors,” said Dr. Palop. “Even with a declining orchestra, they can restore the rhythms and harmony needed for cognitive functions.”
The findings could eventually lead to the development of new treatment options for patients with Alzheimer's disease, he noted.
“Besides the applications this cell engineering and transplantation approach may find in regenerative medicine, our findings support the broader concept that enhancing the function of interneurons can counteract key aspects of Alzheimer's disease,” adds Lennart Mucke, M.D., director of the Gladstone Institute of Neurological Disease.
In addition to examining if the cell therapy could be translated from mice to humans, Dr. Palop and his team are working to identify potential drugs as an alternative way to enhance the function of inhibitory interneurons.