UB Researchers Discover Promising Drug Target for Alzheimer’s, Stroke

“If we could find a drug that attaches itself to this site and locks together NMDA receptor subunits, that would be huge for fighting disability from stroke, Alzheimer’s and other neurodegenerative diseases,” says Gabriela K. Popescu, PhD, associate professor of biochemistry and senior author on the study.

The research focuses on the brain’s receptors for the neurotransmitter glutamate, which is implicated in stroke, neurodegenerative disease. glaucoma and other conditions.

The two main glutamate receptors in the brain are NMDA and AMPA receptors. Both play critical roles in human learning and memory; both are made of four subunits organized in pairs called “dimers.”

Because of these similarities, scientists assumed that NMDA and AMPA receptors function in much the same way.

“But when we altered the dimer interface—the site where two subunits come together within each pair—we found that the NMDA receptor works just the opposite of the way that the AMPA receptor works,” Popescu says.

“Cementing this interface in AMPA receptors leads to more activity, whereas we found just the opposite to be true in NMDA receptors.”

By locking the subunits together, the UB researchers reduced NMDA activity and the amount of calcium that enters neurons in response to the neurotransmitter glutamate.

Calcium overload due to overactive NMDA receptors eventually kills neurons and leads to the symptoms that occur after a stroke, and in Alzheimer’s and other neurodegenerative diseases.

“The fact that we could so dramatically reduce NMDA receptor activation by cross-linking the subunits demonstrates for the first time the tantalizing possibility that we may be able to develop new, more effective therapies to treat, or even one day prevent, these devastating diseases,” says Popescu.

The findings present opportunities for researchers to design drugs that would preferentially inhibit a select population of NMDA receptors in the brain, thus reducing the possibility of side effects.

Currently, one of the only existing pharmaceuticals that inhibits the NMDA receptor—the Alzheimer’s drug Namenda—targets a different site within the receptor.

The research paper—titled “NMDA receptor activation requires remodelling of intersubunit contacts within ligand-binding heterodimer”—was published online in the Oct. 11 issue of Nature Communications.

Co-authors are Willliam F. Borschel and Swetha E. Murthy, doctoral candidates in the UB Department of Biochemistry, and Eileen M. Kasperek, senior technician in the department.