Beta-secretase (BACE), an enzyme involved in the formation of the amyloid-beta protein, can also alter the mechanism by which signals are transmitted between brain cells, found researchers at the MassGeneral Institute for Neurodegenerative Disorders. Their results may explain the increased incidence of seizures in Alzheimer’s patients and suggest that potential treatments that block this enzyme may alleviate their occurrence.
“We have found a molecular pathway by which BACE can modulate the activity of sodium channels on neuronal cell membranes,” says study leader Dora Kovacs, Ph.D., director of the Neurobiology of Disease Laboratory in the Genetics and Aging Research Unit.
The investigators first confirmed that the beta2 subunit, which helps to regulate the sodium channels’ activity, can be acted on by BACE and gamma-secretase, releasing a portion of the beta2 molecule from the cell membrane.
A series of experiments using brain tissue from animal models and Alzheimer’s patients revealed a series of cellular events. Elevated levels of the free beta2 segment within the cell appear to increase production of the alpha subunits, which make up the body of the channel, but that those molecules are not incorporated into new channels on the cell surface. The resulting deficit of membrane sodium channels inhibits the passage of neuronal signals into and through the cells, potentially causing seizures.
The report will appear in Nature Cell Biology.