Antibodies Found to Penetrate Neurons to Destroy Alzheimer's-Associated Amyloid

Investigators have gotten closer to understanding how immune-based therapies can treat Alzheimer's disease (AD)--by studying how antibodies go inside brain cells to reduce levels of Alzheimer's-linked amyloid peptides that form plaques between neurons.

"This internalization and activity of the antibody within the cell was a big surprise, and something we really haven't appreciated in neurological medicine. It gives us new hope for the use of immunotherapy against Alzheimer's, while casting intriguing new light on other disease processes,” stated senior author of the study, Dr. Gunnar Gouras, associate professor of neurology and neuroscience at Weill Cornell Medical College (New York, NY, USA) and associate attending neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

The study was published in the May 1, 2007, online edition of the Journal of Biological Chemistry.

There are currently no effective treatments to combat AD. For many years, the theory of an immune-based vaccine therapy against Alzheimer's has been one of the ultimate goals of research. In fact, in the past, researchers did have some clinical success with an antibody-directed immune therapy. Those expectations were tampered down somewhat after a few individuals came down with a serious, treatment-linked (but nonfatal) meningitis.

"Still, the dream has remained very much alive--especially since we know that antibodies to the beta-amyloid plaques associated with Alzheimer's can cross the blood-brain barrier, gaining access to the brain,” Dr. Gouras explained. He remains one of the leading authorities on beta-amyloid plaques because of earlier studies on its deposition and accumulation between neurons. "One of the things those earlier immunotherapy studies taught us was that antibodies can reduce amyloid plaques, which are a hallmark of the disease. The next logical question was--how does it do that?”

Over the past six years, Dr. Gouras' team took advantage of developments in neuroscience research to help answer that question. They relied on the development of special transgenic mice bred to closely approximate the progress of human AD. In their latest study, the researchers exposed amyloid-filled neurons from these mice to immune antibodies similar to those used in clinical trials. They then examined changes in these cells in the lab, using microscopy, immunofluorescence, and other sophisticated techniques.

"What we found astounded us,” Dr. Gouras says. "Instead of working outside the cell, we discovered that these antibodies to beta amyloid bind with a specific part of amyloid precursor protein [APP]--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 that are found outside and between cells.”

In fact, the antibodies decreased the intracellular amyloid accumulation by approximately one-third, the researchers found. How might antibodies working inside neurons reduce exterior plaque levels? The researchers still are not certain, but they have already ruled out some of the most obvious answers.

"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," noted the study's lead investigator, Dr. 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,” Dr. Tampellini stated.

According to the researchers, it is possible that the antibody is affecting major trafficking processes within the cell, thereby 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,” Dr. Gouras remarked. "More research is needed to clear up that mystery, however.”

What is evident from the study is that immune-based therapy does work to get rid of brain cells of amyloid--giving new momentum to the search for a safe, effective Alzheimer's vaccine. "A cure isn't likely as close as we are hoping for,” Dr. Gouras cautioned, "and new roadblocks to a successful vaccine might arise. But as we better understand how immunotherapy is working, we can better meet those roadblocks head-on.”

Moreover, the finding that antibodies function both inside and outside the cell could have significant implications for the study of other disease conditions, particularly autoimmune disorders, where the immune system misguidedly attacks it own tissues. "Biologists have long understood that antibodies can affect intracellular processes, but it's been woefully under appreciated in medicine,” commented Dr. Gouras. "Hopefully, this will help to change that.”


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