Health & Medicine - Posted by Nancy Ross-Flanigan-Michigan on Tuesday, November 10, 2009 15:46 - 0 Comments
Molecules built to break up Alzheimer’s clumps
U. MICHIGAN (US)—Scientists have developed “bi-functional” small molecules that not only grab metal ions but also interact with peptides that clump to form plaques in the brain.
The discovery shows promise for exploring and treating Alzheimer’s disease, says Mi Hee Lim, assistant professor with joint appointments in the chemistry department and Life Sciences Institute at the University of Michigan. Details about the research were published online this month in the Journal of the American Chemical Society.
Formation of plaque cause cell death, leading to the devastating symptoms of memory loss and other mental difficulties associated with Alzheimer’s.
Though the exact mechanism for amyloid-beta peptide clump formation isn’t known, scientists do know that copper and zinc ions are involved, not only in the aggregation process, but apparently also in the resulting injury. Copper, in particular, has been implicated in generating reactive oxygen species, which can cause cell damage.
One way of studying the role of metals in the process is by sopping up the metal ions with molecules called chelators and then seeing what happens when the metal ions are out of the picture.
When other scientists have done this they’ve found that by removing metals, chelators hamper both amyloid beta clumping and the production of those harmful reactive oxygen species, suggesting that chelators could be useful in treating Alzheimer’s disease.
However, most known chelators can’t cross the blood-brain barrier, the barricade of cells that separates brain tissue from circulating blood, protecting the brain from harmful substances in the bloodstream.
What’s more, most chelators aren’t precise enough to target only the metal ions in amyloid beta; they’re just as likely to grab and disable metals performing vital roles in other biological systems.
“The idea is simple,” says Lim. “We found molecules known for amyloid-beta recognition and then attached metal binding sites to them.”
In collaboration with Ayyalusamy Ramamoorthy, professor of chemistry and associate professor of biophysics, Lim then used NMR spectroscopy to confirm that the new, hybrid molecules still interacted with amyloid beta.
In experiments in solutions with or without living cells, the researchers showed that the bi-functional molecules were able to regulate copper-induced amyloid-beta aggregation, not only disrupting the formation of clumps, but also breaking up clumps that already had formed.
In fact, their molecules performed better than clioquinol, a clinically-available metal chelator that showed promise in early trials with Alzheimer’s patients, but has side effects that limit its long-term use.
“Based on their small size and other properties, we believe our compounds will be able to cross the blood-brain barrier, but we want to confirm that using mouse models,” Lim says.
The researchers also plan experiments to see if their new chelators are as good at preventing and breaking up amyloid-beta plaques in the brains of mice as they are in solutions and cultured cells.
The research was supported by the University of Michigan and the National Institutes of Health.
University of Michigan news: http://www.umich.edu/news/