January 18, 2008

Study seeks Alzheimer’s disease ‘dimmer switch’

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Jeffrey Conn, Ph.D.

Study seeks Alzheimer’s disease ‘dimmer switch’

Researchers at Vanderbilt University Medical Center have found a way to “turn up” the activity of a receptor for a neurotransmitter in the brain that plays an important role in Alzheimer's disease.

Their finding, reported in the current issue of Nature Chemical Biology, could lead to the development of new drugs that can improve cognitive function and reduce psychotic symptoms in patients with the disease.

“Through chemistry, we've now developed compounds that are very specific for a single receptor subtype for the neurotransmitter acetylcholine,” said Jeffrey Conn, Ph.D., the paper's senior author and director of the Vanderbilt Program in Drug Discovery. “After two decades of unsuccessful attempts, people thought it was impossible.”

The key to this unprecedented selectivity was to develop compounds that do not directly activate the receptor in the same way as acetylcholine. Instead, the compounds work like the dimmer switch in an electrical circuit. They turn up the activity of a muscarinic acetylcholine receptor, M4, in a key part of the rat brain — the hippocampus.

The hippocampus, from the Greek words for horse and sea monster, is a seahorse-shaped structure deep in the forebrain that is essential for memory and learning. It is one of the first parts of the brain to be damaged in Alzheimer's disease.

Acetylcholine is a neurotransmitter that, by binding to different receptors throughout the body, can trigger muscle contractions, slow the heartbeat and add to the brain's store of memories. Muscarine, a compound found in certain mushrooms, mimics acetylcholine by binding to some of its receptors.

Researchers have tried for years to find drugs that, by activating muscarinic receptors in the hippocampus, would relieve the symptoms of Alzheimer's disease. These efforts were abandoned because the drugs bound to four different muscarinic receptors, causing serious side effects elsewhere in the body.

In low doses, however, one of the drugs, which preferentially activated M1 and M4 receptors, had anti-psychotic effects. It reduced the hallucinations, delusions, paranoia and outbursts that are among the most troubling manifestations of Alzheimer's disease.

While the drug was not pursued because of side effects, it got Conn to thinking: could he develop compounds that specifically activate only the M1 or M4 receptor?

In previous studies, Conn and his colleagues found they could regulate the activity of another receptor when it bound to the neurotransmitter glutamate by attaching a compound, called an “allosteric modulator” to a secondary site on the receptor.

The same approach was used in the current study to find highly selective allosteric modulators that could “ramp up” the activity of the M4 receptor when it bound to acetylcholine in the rat. The Vanderbilt researchers also have reported finding a “dimmer switch” for the M1 receptor.

Clinical studies suggest that increasing the effects of acetylcholine through its muscarinic receptors can reduce the psychotic manifestations and possibly improve cognitive function in Alzheimer's disease.

“The question is, is it M1 or M4 or both?” Conn asked. “Now we have the tools to pull these things apart.”

Jana Shirey, a graduate student in Conn's laboratory, and Zixiu Xiang, Ph.D., research assistant professor of Pharmacology, were the lead authors of the paper.

Co-authors were Darren Orton, Ph.D., Ashley Brady, Ph.D., Kari Johnson, Richard Williams, Ph.D., Jennifer Ayala, Alice Rodriguez, Ph.D., Jürgen Wess, Ph.D., David Weaver, Ph.D., and Colleen Niswender, Ph.D.

The study was supported by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.