2023 Alzheimer's Association Research Grant (AARG)
Nanoscale Mechanisms of NMDAR Dysfunction in AD
How do molecules that help nerve cells communicate change during Alzheimer’s?
Martin Hruska, Ph.D.
West Virginia University
Morgantown, WV - United States
Background
Glutamate is a chemical compound that helps nerve cells communicate. Nerve cells sense glutamate in their environment by using specialized channels on their surfaces, known as NMDARs (N-methyl-D-aspartate receptors). There are several different types of NMDARs. Each occupies a precise location on the surface of nerve cells. Many NMDARs are found near synapses, which are the specialized structures that nerve cells use to send signals to one another.
Proteins such as beta-amyloid, one of the hallmark brain changes in Alzheimer’s, can interfere with NMDAR function. This can make it difficult for nerve cells to communicate properly. Initial research by Dr. Martin Hruska and colleagues shows beta-amyloid may change the distribution of NMDARs on the surfaces of nerve cells, which might contribute to problems with nerve cell communication seen in Alzheimer’s.
Research Plan
Dr. Hruska plans to determine how short- and long-term exposure to beta-amyloid impacts the distribution of NMDARs on the surfaces of nerve cells. They will use nerve cells grown in laboratory dishes and genetically engineered Alzheimer’s-like mice for their experiments. First, they will expose nerve cells to fluorescent molecules that can bind to and “highlight” specific types of NMDARs. Using specialized microscopes, Dr. Hruska’s team will then track the quantity and movement of NMDARs following short-term beta-amyloid exposure on nerve cells in laboratory dishes. They will then perform similar experiments using brain tissue samples collected from Alzheimer’s-like mice to understand how long-term beta-amyloid exposure might influence NMDAR organization on the surfaces of nerve cells.
Next, Dr. Hruska’s team will test the functions of NMDARs that are located on small and large nerve cell projections, known as spines. They will expose nerve cells growing in laboratory dishes to beta-amyloid and then measure calcium molecules that flow through the NMDAR channels as an indicator of NMDAR function. Calcium is a key component of brain communication networks and an indicator of nerve cell health. By comparing calcium levels in small versus large nerve cell spines, Dr. Hruska hopes to understand the kinds of NMDARs that are most vulnerable to the effects of beta-amyloid during Alzheimer’s.
Impact
NMDARs are currently being investigated as targets for drugs designed to help restore nerve cell communication during Alzheimer’s. This study offers detail about exactly how different types of NMDARs function in the context of Alzheimer’s, and how the presence of beta-amyloid might change the availability of these emerging drug targets on the surfaces of nerve cells. Results from this work could be used to help refine and inform Alzheimer’s drug development.