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The loss of the sense of smell, one of the earliest known impairments caused by Alzheimer's disease, can be restored by removing a plaque-forming protein in a mouse model of the disease, researchers at Case Western Reserve University have found. The study confirms that the amyloid beta protein causes the loss (issue of The Journal of Neuroscience, Nov. 2, 2011).
"The evidence indicates we can use the sense of smell to determine if someone may get Alzheimer's disease and use changes in sense of smell to begin treatments, instead of waiting until someone has issues learning and remembering," said lead investigator Daniel Wesson, PhD. "We can also use smell to see if therapies are working."
While smell loss can be caused by a number of ailments, exposures and injuries, it has been identified as an early sign of Alzheimer's since the 1970s. The new research shows how and where in the brain this happens and that the impairment can be treated.
"Understanding smell loss will hold some clues about how to slow down this disease," Dr. Wesson said.
Currently, there is no effective treatment or cure for Alzheimer's, which is marked by eroding senses, cognition and coordination, leading to death. The disease affects 5.3 million Americans, and that number is expected to triple to 16 million by 2050, according to the Alzheimer's Association.
Dr. Wesson worked with Anne Borkowski, a researcher at the Nathan S. Kline Institute in Orangeburg, NY; Gary Landreth, professor of neuroscience at Case Western Reserve School of Medicine; and Ralph Nixon, Efrat Levy and Donald Wilson, of the New York University School of Medicine.
The researchers found that just a tiny amount of amyloid beta causes smell loss in mouse models. Amyloid beta plaque accumulates first in parts of the brain associated with smell, well before accumulating in areas associated with cognition and coordination.
The olfactory bulb, where odor information from the nose is processed, becomes hyperactive early on. Over time, however, the level of amyloid beta increases in the olfactory bulb, and the bulb becomes hypoactive. The mice studied spent more time sniffing but failed to remember smells and became incapable of telling the difference between odors.
The same pattern is seen in people with the disease. They become unresponsive to smells as they age.
While losses in the olfactory system occurred, the rest of the mouse model brain, including the hippocampus - which is a center for memory - continued to act normally early in the disease stage.
"This shows the unique vulnerability of the olfactory system to the pathogenesis of Alzheimer's disease," Dr. Wesson said.
The researchers sought to reverse the effects by giving the mice a synthetic liver x-receptor agonist, a drug that clears amyloid beta from the brain. After two weeks on the drug, the mice could process smells normally. After withdrawal of the drug for one week, impairments returned.
Dr. Wesson and his team now are working to determine how amyloid spreads throughout the brain to learn methods to slow disease progression.
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