Potential New Target For Alzheimer’s Disease Treatment Identified
April 29, 2009
Adapted from the University of California - San Diego
A defining hallmark of Alzheimer's disease is the accumulation of the amyloid-beta protein otherwise known as "senile plaques," in the brain's cortex and hippocampus, where memory consolidation occurs. Researchers at the University of California, San Diego (UCSD) School of Medicine have identified a novel protein which, when over-expressed, leads to a dramatic increase in the generation of amyloid-beta. Their findings, which indicate a potential new target to block the accumulation of amyloid plaques in the brain, is published in the May 1, 2009 issue of the Journal of Biological Chemistry.
"The role of [this novel] protein, RANBP9, suggests a possible new therapeutic target for Alzheimer's disease," said David E. Kang, Ph.D., Assistant Professor of Neurosciences at UC San Diego and recipient of an BrightFocus Foundation grant to direct this study.
The toxic protein amyloid-beta is produced when the amyloid precursor protein (APP) is "cut" by two enzymes, called beta-secretase and gamma-secretase. However, inhibiting these enzymes in order to stop the amyloid cascade has many negative side effects, as these enzymes also have various beneficial uses in brain cells. So the researchers looked for an alternative way to block the production of amyloid beta. Kang and his colleagues looked for proteins that help amyloid beta shuttle from the brain to the body, where it is broken down into harmless waste products. This shuttling is accomplished by a third enzyme involved in the body's use of cholesterol.
Kang explained that these three components must come together to produce amyloid beta from APP. To test this, the scientists removed RANBP9 from cell, and discovered that 60% less amyloid beta was produced. Madepalli K. Lakshmana, Ph.D., the study's first author, added that "this study is the first to identify RANBP9 as a target to potentially inhibit … amyloid beta peptide generation… As such, a small molecule drug that can reduce the RANBP9 protein levels could offer an effective treatment for Alzheimer's disease." Inhibiting the RANBP9 protein may offer an alternative approach to therapy, by preventing contact between APP and the enzyme that makes the cut essential to produce amyloid plaques," said Kang. The researchers' next step is to verify these findings in animal models.
“A recent survey reported that over half of the US adult population have been affected by Alzheimer's disease,” says Kathleen Honaker, Executive Director for the BrightFocus Foundation, “Dr. Kang's research should remind all of us of the tireless and dedicated work of scientists around the globe working to cure this devastating disease.”
On behalf of its donors, the Alzheimer's Disease Research (ADR) program of the BrightFocus Foundation, is proud to have funded Dr. Kang for this very important work that has identified an exciting new class of molecules with the potential to turn into the next generation of Alzheimer's disease treatments.
In addition, BrightFocus and its donors are proud to have Dr. Koo as a contributor to this research and as the Chairman of its ADR Scientific Review Committee.
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