Piecing together the Alzheimer’s puzzle

In recent years, scientists in the lab of Stephen M. Strittmatter, M.D., Ph.D., Vincent Coates Professor of Neurology, have identified critical steps in the “cascade” of events in which Alzheimer’s disease (AD) destroys brain cells. In 2009 they found that amyloid-beta (A-ß) peptides, a hallmark of AD, bind with prion proteins on the surface of neurons in AD.

By an unknown process, the scientists knew, this coupling activates a molecular messenger within the cell called Fyn. To better understand the process, they screened 81 membrane proteins for their ability to stimulate Fyn in the presence of the A-ß-prion complex. In the Sept. 4 issue of Neuron, they reported that one protein, metabotropic glutamate receptor 5 (mGluR5), bound to both players simultaneously. They also found that mGluR5 is required for the A-ß-prion complex to signal through Fyn. When they blocked mGluR5 in mice with AD, cutting the connection between the A-ß-prion complex and Fyn, deficits in memory, learning, and synapse density associated with AD were restored.

“Of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs,” says Strittmatter, senior author of the study. “This gives us stronger hope that we can find a drug that will work to lessen the burden of Alzheimer’s.”