Mar. 21, 2001 The creation of a new transgenic mouse that makes a mysterious brain chemical may lead to better understanding of why people with Alzheimer’s disease lose their memory.
The neurotransmitter galanin appears to play a role in the disease, and scientists are now trying to figure out how and why. Galanin is normally neuro-protective, following brain injury. One possibility is that the brain overproduces galanin during the early stages of Alzheimer’s in an effort to rescue the afflicted brain – but, over time, the brain’s own attempted cure makes a bad situation worse.
"This could be a sad irony. The body may be detecting the underlying pathology of Alzheimer's and tries to rescue deteriorating brain cells with increased expression of galanin. Very early on in the disease, galanin might even be having beneficial effects," said Dr. Robert Steiner, a professor in the departments of Obstetrics and Gynecology, and Physiology and Biophysics, at the University of Washington School of Medicine. "As the brain attempts to rescue itself with galanin and the disease progresses, the overexpression of galanin may become its own problem. This excess of galanin may contribute to the cognitive decline that Alzheimer's patients and their families so dread. "
The findings of Steiner and colleagues are published in the March 20 issue of Proceedings of the National Academy of Sciences. Co-authors include Dr. Jacqueline N. Crawley, chief of the Section on Behavioral Neuropharmacology, the National Institute of Mental Health; Dr. Elliott J. Mufson, professor in the Department of Neurological Sciences at Rush Presbyterian-St. Luke’s Medical Center in Chicago; and Dr. John Hohmann, who was then a doctoral student in the neurobiology and behavior program at the University of Washington.
If galanin is playing a role in the disease, then what we know as Alzheimer’s could be the result of many parallel events that themselves create complications. Crawley said that galanin will need to be studied along with other possible factors that may underlie the development of this disease.
Steiner is a neuroendocrinologist who developed the transgenic mouse that overexpresses galanin. He did so originally to study the neurotransmitter’s effects on the reproductive system. However, he had been aware that galanin is found in portions of the brain affected in Alzheimer’s victims where substantial numbers of brain cells have been destroyed. At a conference, Steiner started chatting with Crawley, an international expert on the behavorial actions of galanin and the use of mouse models to study neuropsychiatric diseases. The pair decided to put Steiner’s mice through a series of tests to determine their mental function. Steiner’s mice, with their overabundance of galanin, appear to have normal motor and sensory abilities; they are able to normally move and sense things, for example. But they have deficits in higher-order cognitive function – in other words, they have problems performing difficult tasks that require them to remember things.
In one test, mice were required to recall visual cues in a swimming pool to remember the location of an escape platform. The mice with excess galanin had trouble remembering where the platform had been located. This is the same sort of effect seen in Alzheimer’s patients, Crawley said; it’s because of this problem with remembering spatial landmarks that nursing homes with Alzheimer’s patients often use brightly colored walls or other distinctive cues to help patients navigate around their residence.
The mice were also tested to determine if they could remember food odors that they had smelled earlier on other mice. Normally, mice have an excellent memory of scents. But mice with excess galanin were unable to recall whether they had sniffed cinnamon or cocoa on other mice. Olfactory memory and spatial memory rely on different brain mechanisms. So the scientists conclude that these mice have wide-ranging memory problems that mirror memory loss in people suffering from Alzheimer’s.
There is no evidence that galanin itself is the root cause of Alzheimer's. Instead, researchers think it could be a combination of the overabundance of galanin and the loss of certain key brain cells that helps explain why Alzheimer's patients suffer the gradual loss of cognition.
"It may be that galanin is making a bad situation even worse," Crawley said. "The combination of cell death and inhibitory actions of galanin may be responsible for the memory losses that leaves Alzheimer’s patients unable to care for themselves."
Mufson is an expert in neurochemical pathology of Alzheimer’s and studies the deterioration of cholinergic neurons. Mufson examined the brains of the transgenic mice and found that they have 70 percent fewer cholinergic neurons in the horizontal limb of the diagonal band of Broca, similar to what happens in humans with Alzheimer’s.
"These mice are an example of a model of at least part of the Alzheimer’s syndrome," Mufson said. "Now that we have this model, we can study the effects of the overexposure of galanin and how to block it."
Now that the transgenic mouse model may be used to test treatments for Alzheimer’s, researchers are trying to determine what happens if mice are treated with a galanin receptor antagonist that blocks the effects of excess galanin, Crawley said. This may not be easy because there are at least three galanin receptor subtypes, and possibly more.
Researchers are also looking into whether galanin works in concert with another factor implicated in Alzheimer’s: amyloid plaques. There could well be a connection; Professor Tomas Hökfelt at the Karolinska Institute in Stockholm found that mice bred for amyloid plaques also have an excess of galanin, but researchers do not know exactly why.
A drug that blocked galanin might be able to slow or reverse the mental damage caused by the disease. Because Alzheimer’s is so complicated, it may be that someday people have to take a whole cocktail of drugs, such as anti-amyloids, galanin antagonists and anti-cholinesterases, Mufson said.
SIDEBAR: What’s so important about galanin?
Galanin is a neuropeptide, composed of amino acids. It is found throughout the body and brain. It does different things in different parts of the body. It affects the body's secretions of growth and reproductive hormones, and may regulate food intake and body weight. It also plays a role in peripheral nerves and organs.
Scientists have known that galanin has something to do with learning and memory and is involved in brain function, and disorders such as epilepsy. When a nerve is cut or injured, the neuron produces extra galanin, possibly to repair or modulate the damage. The production of galanin may be one way that the body tries to repair nerve damage. Galanin's appearance during Alzheimer's is mysterious. Alzheimer's is associated with degeneration of the brain and of cognitive function. People with Alzheimer's have fewer brain cells and less of some important neurotransmitters than people without the disease.
However, there is no shortage of the neurotransmitter galanin. Autopsies show that people with Alzheimer's have twice as much galanin in certain areas of the brain as peers who die of something else. In Alzheimer’s disease, excess galanin appears in the frontal cortex, surrounding the dying cholinergic neurons so characteristic of Alzheimer’s. About 4 million Americans have Alzheimer’s disease.
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