DURHAM, N.C. -- The ability to recognize familiar objects and companions is lost when levels of a protein crucial for recycling a chemical messenger in the brain are reduced, mimicking some of the symptoms of Alzheimer's disease, an international team led by Duke University Medical Center scientists has discovered.
Mice genetically engineered to have modest defects in this recycling protein display symptoms that resemble those in Alzheimer's, such as the inability to remember familiar faces, according to the researchers. The crucial protein recycles a chemical called acetylcholine that carries messages between nerves cells, the scientists said.
"By using these genetically engineered mice as models of Alzheimer's, we can learn more about the neuronal circuitry of the brain, and perhaps even discover new ways to alleviate the symptoms of this devastating disease," said senior study investigator Marc G. Caron, Ph.D., James B. Duke professor of cell biology.
The team reports its findings in the Sept. 7, 2006, issue of the journal Neuron. The research was supported by the National Institutes of Health and American Health Assistance Foundation.
Acetylcholine is a neurotransmitter that carries a number of vital signals from one nerve cell, or neuron, to another. Normally, when a signal needs to travel through the brain, neurons release acetylcholine to transport the signal across the gap, or synapse, between neurons. Acetylcholine is stored in tiny hollow spheres, called vesicles, that bud off of the end of the neurons. A kind of protein pump, called a transporter, located in each neuron controls the storage and release of acetylcholine from these vesicles, recycling the neurotransmitter back to the nerve cell vesicles in preparation for the next burst of signal.
It is this acetylcholine transporter protein that the researchers targeted by disrupting the gene that controls its production.
"Acetylcholine is important for every function in the body -- breathing, eating, walking, practically everything," Duke's Caron said. "If we knocked out the function of the protein completely, then the mice would die. So instead, we just knocked its function down to a low level."
In the study, the researchers took advantage of a built-in trait of their animal models -- that is, the fact that mice are innately curious and tend to explore new objects and companions extensively by sniffing and touching. The scientists ran mutant mice, in which the acetylcholine transporter gene was defective, through a series of tests to evaluate their performance in behavioral tasks. They ran normal mice through the same tests to serve as a control group.
The first test assessed the mice's ability to discriminate unfamiliar objects. The researchers gave the mutant and normal mice two objects to explore, and then took the objects away. A short time later, the scientists gave the mice back one of the objects, along with a nonfamiliar object. Both the normal and mutant mice initially explored the two objects to the same degree, but after the break the mutants had trouble remembering the familiar object, said lead study investigator Vania F. Prado, Ph.D., an associate professor of biochemistry at Universidade Federal de Minas Gerais, in Belo Horizonte, Brazil.
The second test of memory was similar to the first, but instead of giving the mice objects to explore, the scientists introduced a new mouse into the cage of their test subjects. The normal mice extensively explored the "intruder" mouse, but over time they showed less and less interest, the researchers said. This behavior, they said, demonstrated that the normal mice had become familiar with the intruder. In contrast, the mutant mice failed to recognize the intruder even after several meetings, thus displaying a defect in what the researchers called "social memory."
These findings suggested that the decreased levels of acetylcholine in the mutant mice resulted in their trouble with social memory, the scientists said.
To determine if this theory was true, the researchers set out to correct the behavioral defect by treating the mice with drugs that increase levels of acetylcholine in the brain. Called cholinesterase inhibitors, the drugs block a brain enzyme that typically breaks down acetylcholine, thus leaving more of the neurotransmitter available for sending the signals involved in learning and memory. Physicians give cholinesterase inhibitors to people with Alzheimer's to slow their memory loss and enable them to perform daily tasks, lessening the symptoms of the disease.
Mutant mice treated with the drugs, when run through the same tests, recognized intruder mice after several meetings, the researchers said, adding that this observed improvement in the performance of social recognition confirmed that the defects stemmed from the reduced amounts of acetylcholine.
"Now we can use our animal model to screen for similar drugs that can improve the function of acetylcholine in the brain," said Marco A. M. Prado, Ph.D., an associate professor of pharmacology at Universidade Federal de Minas Gerais and senior investigator of the study. "This is of importance because decreases in acetylcholine are thought to be relevant for the diminishing cognitive function found in aging and also are believed to be associated with some of the behavioral and cognitive symptoms in Alzheimer's disease."
Approximately 4 million Americans have Alzheimer's disease, and 100,000 people die from the disease each year.
Other researchers participating in the study included Amy J. Ramsey, Tatyana D. Sotnikova, Hyung-Gun Kim, Hui Quan, William C. Wetsel, and Raul R. Gainetdinov of Duke University Medical Center; Cristina Martins-Silva, Braulio M. de Castro, Ricardo F. Lima, Vinicius R. Cota, Marcio F. D. Moraes, Marcus V. Gomez, Christopher Kushmerick, Grace S. Pereira, Ernani Amarai, Janaina Koenen and Cristina Guatimosim of Universidade Federal de Minas Gerais; and Daniela M. Barros, Maria R. Ramirez, Janine L. Rossato, and Ivan Izquierdo of Pontificia Universidade Catolica de Rio Grande do Sul, in Porto Alegre, Brazil.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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