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An enzyme that drives plaque formation in Alzheimer's disease also has a key role in normal axonal development and targeting, which might be disrupted by a new class of drugs that inhibit the enzyme, studies in mice suggested.
Animals with a genetically engineered deficiency in the enzyme BACE1 produced offspring with mistargeted olfactory sensory neuron axons, indicating defective axon guidance.
As compared with wild-type mice, the enzyme-deficient offspring had smaller olfactory bulbs that often had malformed glomeruli with randomly oriented, poorly bundled olfactory sensory neuron axons, according to a report published online in Molecular Neurodegeneration.
The findings suggest that newly developed BACE1 inhibitors might disrupt neuronal function and possibly worsen the memory impairment the drugs were designed to treat.
"Let's proceed with caution," Robert Vassar, PhD, of Northwestern University in Chicago, said in a statement. "We have to keep our eyes open for potential side effects of these drugs."
Vassar headed a team of researchers that discovered BACE1 and uncovered its role in amyloid plaque formation, a hallmark finding in the brains of Alzheimer's patients. The observations helped fuel ongoing research and development of BACE1 inhibitors for treatment of Alzheimer's disease.
Aside from the link to amyloid plaque, little was known about BACE1 function. BACE1-deficient mice exhibit hippocampus-based memory deficits, have abnormal EEG findings, and are prone to seizures, Vassar and co-authors wrote. Hypomyelination is another characteristic of mice with genetically engineered enzyme deficiency.
The finding that BACE1 co-localizes with presynaptic neuronal markers has indicated that the enzyme has a role in the development and function of axons or terminals. Studies have also indicated that axon guidance molecules might be targets of BACE1, suggesting a possible role for the enzyme in axon guidance.
To learn more about BACE1 function, investigators studied mice that are homozygous for BASE1 deficiency. Specifically, they examined the role of BACE1 in axon guidance of olfactory sensory neurons, a well-established model of axon targeting.
The highest levels of BACE1 in the olfactory bulb are found in the olfactory sensory neuron axon terminals in glomeruli, suggesting a role for the enzyme.
Subsequent studies revealed several key findings, which were reported simultaneously at the American Association for the Advancement of Science meeting in Vancouver. As compared with wild-type animals, BACE1-deficient mice had:
- Smaller olfactory bulbs that weighed significantly less than those of wild-type animals (P=0.00856), suggesting perturbed olfactory sensory neuron axon guidance.
- Diminished visual clarity of olfactory sensory neuron axon bundles and glomeruli under magnification, suggesting abnormal organization or structure of axons.
- Axon guidance defects in olfactory sensory neurons that expressed specific odorant receptors.
"It's like a badly wired house," said Vassar. "If the electrician doesn't get the wiring pattern correct, our lights won't turn on and the outlets won't work."
The observed defects in the olfactory system of the enzyme-deficient mice probably originates in the brain, quite possibly the hippocampus, Vassar continued. If true, the hippocampus would be particularly vulnerable to BACE1 inhibition, which might induce and perpetuate disruption of axon guidance.
"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."
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