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BACE1 Inhibitor Drugs For Alzheimer's Disease May Cause Side Effects

Cautions raised after brain wiring defects found in mice with no BACE1 gene

January 6, 2012
Source:Molecular Neurodegeneration

Alzheimer's disease (AD) therapies currently being tested in clinical trials may cause unwanted side effects, according to new research from Northwestern University. Scientists are now raising cautions about drugs designed to inhibit BACE1, an enzyme that acts as a molecular pair of scissors cutting up proteins that form the clumps thought to cause AD.

“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,” said Robert Vassar, a Northwestern University Professor and lead author of the study recently published in Molecular Neurodegeneration, the official journal of the BrightFocus Foundation. “The possibility exists, based on our findings, that these drugs could cause unwanted side effects or defects in the wiring of the brain or peripheral nervous system.”

Vassar's recent study is the first to identify a role of BACE1 in axon guidance, or the process by which axons, the part of a neuron that transmits signals, 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—or the sense of smell —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 can cause defects.

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.

Molecular Neurodegeneration (MN) publishes peer-reviewed, original scientific research on the causes of neurodegenerative diseases, like Alzheimer's or Parkinson's, and on the pre-clinical testing of potential therapies for these devastating diseases. The open access publishing model provides articles for free to the general public as well as scientists, clinicians and other healthcare practitioners. MN now ranks 30th among 237 neuroscience journals published worldwide with an impact score of 5.36. For more information visit: www.molecularneurodegeneration.com.

Original Article: The Alzheimer's beta-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb.

Tharinda W Rajapaksha, William A Eimer, Thomas C Bozza and Robert Vassar

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