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A team of Weizmann scientists has gained new insight into the effects of a newly approved drug, rivastigmine, in treating Alzheimer’s disease, a debilitating brain disease causing memory loss in around 10% of the elderly. The study was published in the American Chemical Society journal Biochemistry.
“The results were surprising,” says Prof. Joel Sussman, of the Structural Biology Department.“They show that we can safely treat Alzheimer’s disease with much lower quantities of rivastigmine, thus minimizing unwanted adverse effects.” Prof. Joel Sussman's research is supported by the Jean and Jula Goldwurm Memorial Foundation, Charles A. Dana Foundation, Irwin Green Research Fund in Brain Development, the Joseph and CeilMazerCenterfor Structural Biology, Helen & MiltonA.KimmelmanCenterfor Bio-molecular Structure & Assembly. Sussman is the incumbent of the Morton and Gladys Pickman Chair in Structural Biology.
The drug, currently sold as ExelonTM, helps slow memory loss of Alzheimer patients. However, its mechanism of action at the molecular level had not been studied prior to this research, which was conducted by Sussman, Prof. Israel Silman of the Neurobiology Department, and Ph.D. student Pazit Bar-on.
Alzheimer’s disease involves deterioration of nerve cells releasing a substance called acetylcholine, which carries messages between brain cells. The lack of acetylcholine in Alzheimer's patients is compoun-ded by the action of an enzyme called acetylcholinesterase (AChE), which rapidly breaks down acetylcholine. The desired effect of Alzheimer drugs like rivastigmine is to inhibit AChE long enough to adequately raise the levels of acetylcholine.
“We wanted to see how long it takes AChEs to return to normal, or become ‘reactivated,’ after inhibition by the drug,” says Silman. Testing rivastigmine on various types of AChE (extracted from an electric ray, the fruit fly and humans), the team was surprised to find that inhibition was almost irreversible, with little reactivation over a period of days.
To explain this at the molecular level, the scientists took snapshots of rivastigmine bound to AChE by projecting X-rays onto crystals of rivastigmine combined with AChE, and observing the X-rays' diffraction patterns. They then built a molecular map showing the spatial arrangement of all the atoms of AChE and rivastigmine.
Using these maps, the scientists found why the inhibition of AChE by the drug is nearly irreversible: after binding to AChE, rivastigmine breaks in two and moves some of AChE's atoms, making it difficult for it to return to an active state.
The maps provide important information for designing novel chemicals that might fight Alzheimer's more effectively and with less side effects.
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