Researchers at the Scripps Research Institute had some unexpected findings when searching for genes that influence the amount of amyloid that deposits as brain plaques in Alzheimer's disease. Through an extensive gene hunt, the team identified three candidate genes that seemed to offer protection in mice from brain amyloid accumulation and deposition. But to their surprise, they discovered that lower expression in the liver - not the brain - was responsible for the protection.

The study was published online today in The Journal of Neuroscience Research.

"This unexpected finding holds promise for the development of new therapies to fight Alzheimer's," said Scripps Research Professor Greg Sutcliffe, who led the study. "This could greatly simplify the challenge of developing therapies and prevention."

Their findings suggested that significant concentrations of beta amyloid might originate in the liver, before entering the brain through the blood stream. If true, blocking production of beta amyloid in the liver should protect the brain.

To test their hypothesis, Sutcliffe's team set up an in vivo experiment using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. "We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice," Sutcliffe said, "and one would predict in humans, too."

The mice were administered imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. More importantly for this study - Gleevec has poor penetration of the blood-brain barrier in both mice and humans.

"This characteristic of the drug is precisely why we chose to use it," Sutcliffe explained. "Because it doesn't penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease."

The mice were injected with Gleevec twice a day for seven days; then plasma and brain tissue were collected, and the amount of beta amyloid in the blood and brain was measured.

The findings: the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer's.

As for the future of this research, Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development.

To learn more, please visit the official news release.