Alzheimer’s disease drugs now being tested in clinical trials may have potentially adverse side effects, according to new Northwestern University research. A study with mice suggested that the drugs could act like a bad electrician, causing neurons to be miswired and interfering with their ability to send messages to the brain.
The drugs are designed to inhibit BACE1, the enzyme Robert Vassar, professor of cell and molecular biology at Northwestern University Feinberg School of Medicine, originally discovered, reports the university. BACE1 promotes the development of the clumps of amyloid plaque that are a hallmark of Alzheimer’s. It acts as a molecular scissors, cutting up and releasing proteins that form the plaques. Drug developers believed blocking the enzyme might slow the disease.
But in Vassar’s new study, published in the journal Molecular Neurodegeneration, he found BACE1 also has a critical role as the brain’s electrician. In that role, the enzyme maps out the location of axons, the wires that connect neurons to the brain and the rest of the nervous system. This mapping is called axonal guidance.
Working with mice from which BACE1 was genetically removed, Vassar discovered the animals’ olfactory system used for the sense of smell was incorrectly wired. The axons of the olfactory neurons were not wired properly to the olfactory bulb of the brain. The findings show the key role of BACE1 in axonal guidance.
“Let’s proceed with caution,” said Vassar. “We have to keep our eyes open for potential side effects of these drugs.” Ironically, he says, the drugs could impair memory.
“It’s not all bad news,” Vassar said. “These BACE1 blockers might be useful at a specific dose that will reduce the amyloid plaques but not high enough to interfere with the wiring. Understanding the normal function of BACE1 may help us avoid potential drug side effects.”