Therapy for Alzheimer's disease may cause side effects

Alzheimer’s disease (AD) affects an increasing number of people and research continues to develop new treatments, many of which are currently undergoing clinical trials.  However, new research suggests that one such treatment using drugs to inhibit BACE1 may cause unwanted side effects.

Robert Vassar, lead author of the study recently published in Molecular Neurodegeneration,  says “We are in desperate need of something that can treat or prevent Alzheimer’s disease, but at the same time we have to be on the lookout”.  Vassar’s recent study is the first to identify a role of BACE1 in axon guidance, or the process by which axons connect and ensure communication between neurons. Defects result when the process of connecting axons goes awry.

Simply put, such defects in brain wiring can be likened to defects in the wiring of a house.  “You have to wire correctly in order to get electricity into the house to turn on the lights, but if the wiring is not correct the lights won’t function,” Vassar said. “In humans, the brain automatically accomplishes correct wiring through axon guidance.”

However, BACE1 inhibitors may impede this normal process as evidenced by the researchers’ discovery of wiring mistakes in the brains of animal models. By using the olfactory system as a model of axon guidance, the researchers showed that when BACE1 is genetically removed from mice, axons of olfactory sensory neurons were not able to wire properly to the olfactory bulb of the brain. Such findings demonstrate the role of BACE1 in axon guidance, and how inhibiting BACE1 “could cause unwanted side effects or defects in the wiring of the brain or peripheral nervous system.”

While researchers speculate that there may be other neuron systems that require the activity of BACE1 for proper wiring, understanding the molecular basis of new physiological functions for BACE1 may eventually aid in the development of therapies with workarounds for side effects.

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