Alzheimer’s medications currently in trial may actually act like a bad electrician, miswiring neurons and interfering with their ability to communicate with the brain, according to new Northwestern Medicine research.
The problematic side effects were found by Robert Vassar, the scientist whose original study led to the development of the drugs designed to inhibit BACE1—the enzyme Vassar discovered that promotes plaque development.
BACE1 is likened to a pair of molecular scissors, cutting up and releasing proteins that form plaque. Therefore, drug developers thought that if the enzyme were blocked, the disease would slow down.
“Let’s proceed with caution,” said Vassar, professor of cell and molecular biology at Northwestern University Feinberg School of Medicine. “We have to keep our eyes open for potential side effects of these drugs.” Ironically, he says, the drugs could impair memory.
In Vassar’s new study, he discovered that BACE1 also plays a critical role as the brain’s electrician. Specifically, the enzyme maps out the location of axons, the wires that connect neurons to the brain and the nervous system. This mapping is known as ‘axonal guidance.’
Studying mice from which BACE1 was genetically removed, Vassar discovered that the axons in the rodents’ olfactory system – used for the sense of smell—were not wired properly to the olfactory bulb of the brain. The research proved the role of BACE1 in axonal guidance.
“It’s like a badly wired house,” Vassar said. “If the electrician doesn’t get the wiring pattern correct, your lights won’t turn on and the outlets won’t work.”
If the axons aren’t correctly connected in the olfactory system, Vassar said, the problem probably exists elsewhere in the brain and nervous system. For example, the hippocampus could be especially vulnerable to BACE1 blockers, he added, because its neurons are continually being reborn, which may play a role in forming new memories. The neurons must grow new axons which will connect them with new targets. Axonal guidance is a continuous need.
“It’s not all bad news,” Vassar noted. “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.”
The research is published in the journal Molecular Neurodegeneration.
Source: Northwestern University