2022 Alzheimer's Association Clinician Scientist Fellowship (AACSF)
Mapping and modeling interneuron dysfunction in Alzheimer’s Disease
Can damage to certain nerve cells linked to brain cell communication promote Alzheimer’s disease?
Kevin Chen, M.D.
University of Michigan
Ann Arbor, MI - United States
Background
Research suggests that specific nerve cells called interneurons are selectively vulnerable to damage during Alzheimer’s. The loss of a small number of these cells can disrupt the activity of synapses, the tiny connections between nerve cells that help the cells communicate with one another. Studies have also found that interneurons in the hippocampus (a brain region important for memory) may be vulnerable to damage from beta-amyloid, the protein that accumulates into hallmark plaques in the Alzheimer’s brain. Scientists, however, remain uncertain exactly how interneuron levels and interneuron activity decrease in Alzheimer’s.
Research Plan
For their research grant, Dr. Kevin Chen and colleagues will study Alzheimer’s-related interneuronal damage. First, using genetically engineered Alzheimer’s-like mice, they will analyze the transcriptomes (or collections of all gene (DNA) readouts) of the interneurons in the mice. The study of a transcriptome reveals which genes are turned “on” and “off” in a cell in response to an environment or disease state. The researchers will also “map” where in the brain certain interneuron-related genetic changes take place. This type of analysis has not been done on interneurons before, and Dr. Chen’s team plans to use the results to identify specific genes and genetic changes that may promote Alzheimer’s.
Next, the investigators will develop and study interneurons developed from induced Pluripotent Stem Cells (iSPCs). iSPCs are stem cells derived from adult skin cells, and they can be engineered into any type of cell in the body. Dr. Chen and colleagues will engineer their iSPC interneurons from the skin cells of individuals who had Alzheimer’s, and they will grow the cells in a laboratory dish with other types of nerve cells. They will then determine how their interneurons from individuals with Alzheimer’s alter communication between the other nerve cells. The researchers will also engineer iSPC interneurons with genes that can counteract the dementia-related genetic changes they discovered in their first experiment. These cells will be analyzed to assess how well the “restorative” genes can prevent Alzheimer’s-related damage.
Impact
Results from Dr. Chen’s project will shed new light on the role of interneurons in Alzheimer’s and could lead to novel genetic therapies for preventing or treating dementia.