UMD neuroscientists discover nicotine could play role in Alzheimer's disease therapy

October 12, 2010

A team of neuroscientists has discovered important new information in the search for an effective treatment for Alzheimer's disease, the debilitating neurological disorder that afflicts more than 5.3 million Americans and is the sixth-leading cause of death in the United States. 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."

Lee is optimistic about the potential of this discovery, but also says that behavioral studies still need to be conducted to determine if BACE1 knockout mice treated with nicotine will behave normally. Her colleague at Johns Hopkins University, Philip C. Wong, professor of pathology and neuroscience and a co-author on this study, will be conducting these behavior studies as a follow up.

"If you tag along nicotine or anything that can activate this receptor along with the BACE1 inhibitor, then you probably can recover the function better," Lee asserts. "It is an exciting development because nicotine is an already known drug that could be easily used therapeutically with Alzheimer's treatment."

Until recently, challenges in getting a drug that could pass through the blood-brain barrier prevented the development of an effective BACE1 inhibitor drug for use in humans, but recently scientists have developed one that can be taken orally. The University of Maryland and Johns Hopkins University are filing a patent application on the therapeutic treatment that Lee and her colleagues have developed targeting the Alpha7 nicotine receptor. It is possible that this therapy may be one day packaged with BACE1 inhibitor drugs to treat Alzheimer's disease and block its progression.
-end-
"Mossy Fiber Long-Term Potentiation Deficits in BACE1 Knock-Outs Can Be Rescued by Activation of Alpha7 Nicotinic Acetylcholine Receptors" was written by Hui Wang, Lihua Song, Angela Lee, Fiona Laird, Philip C. Wong, and Hey-Kyoung Lee.

University of Maryland

Related Nicotine Articles from Brightsurf:

Nicotine vapour more rewarding for adolescents than adults
University of Guelph researchers are the first to discover that adolescents react differently to e-cigarette vapour than adults.

Understanding the link between nicotine use and misuse of 'benzos'
Lately, misuse of prescription benzodiazepines (such as alprazolam or Xanax, and diazepam or Valium) has been linked to nicotine use.

Popular electronic cigarette may deliver nicotine more effectively than others
When it comes to nicotine delivery, not all electronic cigarettes are created equally, according to Penn State researchers.

Fetal nicotine exposure harms breathing in infants
Exposure to nicotine during development inhibits the function of neurons controlling the tongue, according to research in newborn rats recently published in eNeuro.

Diabetes drug relieves nicotine withdrawal
A drug commonly used to treat Type II diabetes abolishes the characteristic signs of nicotine withdrawal in rats and mice, according to new research published in JNeurosci.

The nicotine in e-cigarettes appears to impair mucus clearance
E-cigarette vaping with nicotine appears to hamper mucus clearance from the airways, according to new research published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

Truth telling about tobacco and nicotine
In 'Truth Telling about Tobacco and Nicotine,' PRC researchers explain that, although there is agreement among researchers about evidence that vaping can be less harmful than combustible cigarettes, the tobacco control community remains divided about how to communicate -- or even whether to communicate -- information about the relative risks of tobacco and nicotine products.

This is a neuron on nicotine
Newly developed sensors visually illustrate how nicotine affects cells from the inside out.

New data suggests nicotine while pregnant alters genes
A University of Houston biomedical research team is reporting that a possible cure for addiction may be found by following the pathways of significantly altered dopamine neurons in newborns who were chronically exposed to nicotine in utero.

Ex-smokers might be better off with high rather than low nicotine e-cigs
Vapers using low rather than high nicotine e-cigarettes may be using their devices more intensely, potentially increasing the risk of exposure to toxins in the vapour, according to new research funded by Cancer Research UK and published in Addiction today.

Read More: Nicotine News and Nicotine Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.