Neuroscientists discover connection between nicotine and Alzheimer’s disease

Hey-Kyoung Lee, associate professor in the University of Maryland Department of Biology, and her research team have shown that they may be able to eliminate debilitating side effects caused by a promising Alzheimer’s drug by stimulating the brain’s nicotine receptors.

Scientists believe that an over-production of a peptide called A-beta in the brain is the cause of Alzheimer’s and are developing drug treatments that prevent the action of the enzyme BACE1, which produces A-beta.

But Lee and her team, including University of Maryland and Johns Hopkins University researchers, previously demonstrated that eliminating — or “knocking out” — the BACE1 enzyme in laboratory mice caused some of the test animals to become confused and aggressive. “The mice exhibit signs of schizophrenia and memory loss when you block the enzyme,” says Lee.

“BACE1 is a very promising drug target, but you have to overcome these obviously debilitating side effects to effectively treat Alzheimer’s disease.”

Lee and her colleagues have been searching for a solution that could circumvent the abnormal brain function and behavioral side effects caused by BACE1 inhibition, and they think they may have found it.

They pinpointed the receptor that is targeted by nicotine, the Alpha7 nicotinic acetylcholine receptor, as a potential therapeutic target. A paper describing their breakthrough appears in the current issue of the Journal of Neuroscience.

“By stimulating the Alpha7 receptor with nicotine, we were able to recover normal brain function,” explains Lee. “We are very hopeful that this will be a way to overcome the deficits seen with the BACE-1 knockouts.”

The research group pinpointed the brain dysfunction to the regulation of calcium uptake by neurons. Calcium triggers the release of neurotransmitters, the chemicals which transmit signals from a neuron to a target cell across a synapse.

“The mice with BACE1 knockouts have less calcium signaling in the pre-synaptic neuron, and that is why they were releasing less neurotransmitters,” Lee says. “We looked at what receptors on the pre-synaptic terminal were linked to a calcium signaling pathway.

This Alpha7 receptor happens to be on one of the pre-synaptic receptors that is a calcium channel, and we thought we could use that to enhance the calcium signaling.”

The research team found that nicotine activated the uptake of calcium, and thus the neurotransmitter release mechanism.

“After treatment with nicotine,” says Lee, “the mice released normal amounts of the neurotransmitter as seen in brains of normal animals.”