NEW YORK (May 3, 2006) -- Breakthrough discoveries are pushing back the origins of Alzheimer's disease to an early breakdown in trafficking within brain cells, according to researchers at the Weill Medical College of Cornell University in New York City.
Experts have long known that a buildup of beta-amyloid protein "plaques" around and between neurons is a hallmark of Alzheimer's disease.
But they've also known that neurological decline can occur prior to this extra-cellular buildup.
"Our work is showing that, long before this extracellular phenomenon occurs, beta-amyloid is building up inside neurons -- specifically, on intracellular trafficking structures called multivesicular bodies," explains Dr. Gunnar Gouras, director of the Laboratory of Alzheimer's Disease Neurobiology and associate professor of neurology and neuroscience at Weill Cornell Medical College.
"In our latest study -- conducted using brain cells from mice engineered to develop an Alzheimer's-like illness -- we find that this gradual accumulation of beta-amyloid hinders the intracellular trafficking of neural receptors in a very specific way," he says.
"The brain cell isn't killed, but it is impaired in its function. And all of this occurs long before we see any evidence of plaque buildup outside the cell," Dr. Gouras says.
He says the work is greatly expanding our understanding of the origins of Alzheimer's disease, and pointing to new ways to fight it.
The findings appear in the April 26 issue of the Journal of Neuroscience.
According to the Alzheimer's Association, more than four million Americans now suffer from Alzheimer's disease, with that number expected to quadruple by mid-century. Right now, a few drugs can temporarily ease some illness symptoms, but there is no effective treatment or cure for Alzheimer's.
For a long while, scientists blamed the disease on a clumping of beta-amyloid plaques between cells. But research conducted at Weill Cornell and elsewhere has pushed back the origins of Alzheimer's disease to events occurring inside the cell.
In their latest study, Dr. Gouras' team used cell biological approaches to examine nerve cells extracted from the brains of "transgenic" mice -- mice genetically engineered to develop a disease very similar to Alzheimer's.
The brain cells were extracted long before the mice developed symptoms indicating advanced disease.
Viewed by electron microscopy, the Weill Cornell researchers detected a buildup of beta-amyloid at the outer membrane of an intracellular trafficking structure called the "multivesicular body."
"The multivesicular body is an endosome -- a kind of cargo-carrying body that's used late in endocytosis, the process by which the cell internalizes nutrients and other substances coming in from outside," explains lead researcher Dr. Claudia Almeida, who was a graduate student at the time of the study.
She and her colleagues give much of the credit to their understanding of the multivesicular body to Dr. Frederick Maxfield, chairman of the department of biochemistry at Weill Cornell, and a renowned pioneer in endocytosis research.
Beta-amyloid buildup around the multivesicular body came as no surprise, however -- the team had first discovered this back in 2002.
"The question for us now was, 'how might this abnormal buildup impair nerve cell function?'" Dr. Almeida said.
To find out, the researchers used a fluorescent "tag" to track the progress of a specific protein -- in this case, epidermal growth factor (EGF) -- as it made its way through the endocytosis process.
"We saw no impairment during early endocytosis, but as soon as we got to the later stages, when multivesicular bodies come into play, we spotted an accumulation of EGF in the cell," Dr. Gouras said.
Why might this be happening? According to the researchers, beta-amyloid-linked impairment in the function of multivesicular bodies seems to "gum up the works" when it comes to an important trafficking mechanism called the ubiquitin-proteasome system.
"This system used to be thought of as the cell's 'garbage disposal' -- cutting up and ridding the cell of its biochemical waste," explained co-researcher Dr. Reisuke Takahashi, a pathologist researcher in Dr. Gouras' lab. "But, increasingly, investigators are realizing that it also has a crucial role to play in trafficking and even synaptic processes."
In fact, a breakdown in the ubiquitin-proteasome system has long been implicated in Parkinson's disease and other degenerative brain diseases.
"Alzheimer's has always been the 'odd man out' here," Dr. Gouras says, "but our work suggests it's maybe time to include Alzheimer's on that list."
The bottom line: "We now know that intracellular beta-amyloid buildup is associated with a destruction of specific processes within nerve cells -- even in the absence of extracellular plaque accumulation," Dr. Gouras says.
The finding "opens a new window on the causes of Alzheimer's disease and --potentially -- new targets that researchers might focus on to help prevent it in its earliest stages," he adds.
The study was supported by grants from the Alzheimer's Association, the American Health Assistance Foundation, and the National Institutes of Health.
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