By studying how antibodies work inside brain cells to reduce levels of amyloid peptides linked to Alzheimer's disease, researchers at Weill Cornell Medical College (WCMC) are moving closer to understanding how immune-based therapies may eventually treat the devastating disease.

"This internalization and activity of the antibody within the cell was a big surprise and something we really haven't appreciated in neurological medicine," said Gunnar Gouras, associate professor of neurology and neuroscience at WCMC. "It gives us new hope for the use of immunotherapy against Alzheimer's, while casting new light on other disease processes."

Gouras' research is the "paper of the week" in an upcoming issue of the Journal of Biological Chemistry. It was also published in the journal's May 1 online edition.

There are currently no effective treatments for Alzheimer's disease, which affects over 5 million Americans, according to the Alzheimer's Association. The total could climb to 16 million by 2050.

For years, researchers have considered the prospect of an immune-based therapy among the most promising solutions. Clinical trials have been moderately successful, but treatments have been linked to serious complications.

"Still, the dream has remained very much alive -- especially since we know that antibodies to the beta-amyloid plaques [concentrations of amyloid peptides] can cross the blood-brain barrier, gaining access to the brain," Gouras said. He remains one of the leading authorities on beta-amyloid plaques because of earlier work on its deposition and accumulation between neurons.

"Immunotherapy studies taught us that antibodies can reduce amyloid plaques, which are a hallmark of the disease," he said. "The next logical question was, how?"

Gouras and colleagues used transgenic mice bred to approximate the progress of human Alzheimer's disease. In this study, they exposed amyloid-filled neurons from these mice to antibodies similar to those used in clinical trials. They then examined changes in these cells using high-tech microscopy.

"What we found astounded us," Gouras said. "Instead of working outside the cell, we discovered that these antibodies to beta amyloid bind with a specific part of amyloid precursor protein -- a precursor molecule to beta amyloid -- as it lies on the outside of the affected cell. This complex then gets internalized within the cell, where it works to decrease levels of amyloid peptides, the building block of plaques found outside and between cells."

In fact, the antibodies cut down on intracellular amyloid accumulation by about one-third, the researchers found.

The mechanism is still unclear. But researchers have ruled out some possibilities.

"We found no evidence that the antibody somehow inhibits the activity of either of the two cellular enzymes, secretases, that we know help produce beta amyloid," said author Davide Tampellini, a researcher in the Weill Cornell Laboratory of Alzheimer's Disease Neurobiology. "In fact, if anything the presence of the antibody appears to boost secretase activity."

The antibody may affect key trafficking mechanisms within the cell, increasing the degradation of existing beta amyloid before it makes its way to the surface.

"Most of the data we have supports this degradation model rather than an inhibition of beta-amyloid production," Gouras said. "More research is needed to clear up that mystery, however."

While the study shows that immune-based therapy does work to rid brain cells of amyloid, Gouras warned that a cure is still a long way off.

"New roadblocks may arise," he said. "But as we better understand how immunotherapy is working, we can better meet those roadblocks head-on."

And the discovery that antibodies work both inside and outside cells could have implications for other studies, especially of autoimmune disorders where the immune system mistakenly attacks it own tissues.

"Biologists have long understood that antibodies can affect intracellular processes, but it's been woefully underappreciated in medicine," Gouras said. "Hopefully this will help to change that."

The study's co-authors are Claudia G. Almeida, Jordi Magrane, Reisuke H. Takahashi, Feng Li and Michael T. Lin, all of WCMC. It was funded by the Dana Foundation, the Alzheimer's Association, the American Health Assistance Foundation, the U.S. National Institutes of Health and the Fundacao para a Ciencia e a Tecnologia, Portugal.

Ernie Mundell is a freelance writer in New York.