New insights into early brain circuit breakdown in Alzheimer’s

One of the first parts of the brain affected by Alzheimer's disease is the entorhinal cortex - a region that plays a big role in memory, spatial navigation, and the brain's internal mapping system.

With support from the Commonwealth of Virginia's Alzheimer's and Related Diseases Research Award Fund (ARDRAF), Fralin Biomedical Research Institute at VTC scientists Sharon Swanger and Shannon Farris are working to understand why this area is especially vulnerable. 

Swanger studies how brain cells communicate across synapses in disease-susceptible brain circuits, while Farris focuses on how different circuits in the brain's memory center function at the molecular level. Their overlapping expertise made the collaboration a natural fit.

"We've both been studying how circuits differ at the molecular level for a while," said Swanger, an assistant professor at the research institute. "This new collaborative project brings together my work on synapses and Shannon's on mitochondria in a way that addresses a big gap in the Alzheimer's disease field."

This kind of state-level support is critical. It gives researchers in Virginia the chance to ask questions that may eventually make a difference for people living with Alzheimer's. It's meaningful to be part of research that could help people facing that journey."

Shannon Farris, VTC scientist

A key focus of their research is mitochondria - tiny structures inside brain cells that provide the energy needed for a variety of cellular functions in neurons including synaptic transmission. In Alzheimer's disease, mitochondria stop working properly in the course of the disease.

Farris and Swanger are investigating whether mitochondria in a vulnerable memory-related circuit may become overloaded with calcium, a key signaling chemical for multiple neuronal and synaptic processes. That overload could contribute to the early breakdown of memory circuits.

"The connection between these cells is one of the first to fail in Alzheimer's," Farris said. "We found that this synapse has unusually strong calcium signals in nearby mitochondria - so strong we can see them clearly under a light microscope. Those kinds of signals are hard to ignore. It gives us a model where we can really watch what's happening as things start to go wrong."

To test their hypothesis, the researchers will study brain tissue from healthy mice and mice with certain aspects of Alzheimer's pathology. By comparing how mitochondria function and how brain cells communicate across synapses in each group, they hope to find early signs of stress or failure in the entorhinal cortex–hippocampus circuit.

Swanger and Farris are members of the Fralin Biomedical Research Institute's Center for Neurobiology Research and also faculty in the Department of Biomedical Sciences and Pathobiology of the Virginia-Maryland College of Veterinary Medicine.