For centuries, Chinese doctors have been using a moss called Qian Ceng Ta, or Huperzia serrata, to treat a variety of ills, from swelling to schizophrenia. Now a Weizmann Institute study has shown how this ancient remedy can be used to develop a modern treatment for Alzheimer's disease.
According to one theory, memory loss and other cognitive deficits in Alzheimer patients result from degeneration of the nerve cells that release the message-carrying chemical, acetylcholine. The acetylcholine shortage that ensues is compounded by the action of AChE, the enzyme that breaks down acetylcholine in the body. Two Alzheimer drugs approved by the U.S. Food and Drug Administration, tacrine (Cognex) and E2020 (Aricept), work by inhibiting AChE.
A Qian Ceng Ta extract has recently captured the attention of researchers and physicians in China and the West because it too inhibits this brain enzyme, although it differs markedly in chemical structure from both tacrine and E2020. The extract is currently under investigation in China and elsewhere as a possible Alzheimer drug.
What the new Weizmann Institute study has shown is precisely how a chemical purified from this extract, called Huperzine A (HupA), blocks the enzyme. Using a method known as X-ray crystallography, the scientists solved the 3-D structure of the complex formed by HupA and the enzyme and found a strikingly good fit between the two: HupA slides smoothly into the active site of AChE where acetylcholine is broken down, and latches onto this site via a very large number of subtle chemical links. This binding closes off the enzyme's "cutting" machinery and keeps acetylcholine out of danger.
"It is as if this natural substance were ingeniously designed to fit into the exact spot in AChE where it will do the most good," says crystallographer Prof. Joel Sussman, one of the authors of the study.
"The good fit also means that HupA could be a potent drug even when used in small quantities, so that the risk of side effects would be minimal," according to fellow author, neurochemist Prof. Israel Silman. In any case, these risks are relatively small because HupA is believed to have low toxicity.
The research was carried out by graduate student Mia Raves together with crystallographer Dr. Michal Harel and Profs. Sussman and Silman, all of the Weizmann Institute. It involved close collaboration with Prof. Alan Kozikowski, a medicinal chemist at Georgetown University in Washington, D.C., who was the first to synthesize HupA in a test tube, and Dr. Yuan-Ping Pang, a chemist at the Mayo Clinic in Jacksonville, Florida, who had made theoretical predictions of the HupA-AChE interaction.