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Making the best of a sticky situation
A new discovery at Rensselaer Polytechnic Institute could have far-reaching effects for patients suffering from Alzheimer's disease and other degenerative diseases, thanks to a team of researchers that has developed a new method to design antibodies, specifically ones that can target the protein particles that lead to Alzheimer's disease. Peter Tessier, Assistant Professor of Chemical and Biological Engineering, led the research. He was joined by three Rensselaer graduate students: Moumita Bhattacharya, Joseph Perchiacca and Ali Reza Ladiwala, with the latter two holding the positions of co-first authors.
Antibodies are large proteins created by the immune system in response to biological threats like infection or disease, and they consist of a Y-shaped protein topped with small peptide loops, which bind to the targets they were created to fight. After the antibody has bonded to the target, the immune system sends cells to destroy the threat.
Currently, antibodies are generally made through a process called immunization. A molecule of interest is injected into the immune system, typically of animals, and "the immune system is able to select antibodies that present the right combination of these peptide loops which have sequences in them that would mediate binding to the molecule that you're interested in," says Tessier. The antibody is then recovered from the animal's body, after which it can be examined and reproduced. Though it obviously works, it is an extremely random process that offers very little control, Tessier notes.
"You're randomly varying these peptide loops and picking the needle out of the haystack," he says.
The new method that the researchers discovered involves using the characteristics of the Alzheimer's protein against it. Alzheimer's disease is caused by the Alzheimer's proteins sticking together to form larger particles. The particles, which are toxic to brain cells, damage the healthy cells and brain functions as a result. According to Tessier, the Alzheimer's peptides that result from the proteins sticking together have regions within them that are self-complementary, with smaller segments that stick together in the way that building blocks interlock. The researchers thought that they could use that feature to form an antibody that would naturally stick to the toxic particles, and started with what Tessier called an antibody scaffold, a blank antibody form that is not designed to bind to anything.
"We actually took pieces of the sticky protein, the Alzheimer's protein, and we actually put them in the loops of the antibodies," he explains. "This is a very strange idea; you typically wouldn't think that the sequence of these peptide loops could actually be literally a sequence from the target molecule that you're trying to bind to. And that was exactly our hypothesis, that we could actually use the information about the target molecule, in this case the Alzheimer's protein, and literally graft—it's just like grafting a branch into a tree—we grafted pieces of the Alzheimer's protein into the antibody loop."
While other antibodies have been developed against the Alzheimer's protein, Tessier says that their antibody is unique in that it targets only the toxic aggregates of the protein. Before it's aggregated, the Alzheimer's protein is soluble and not toxic, so the antibodies are capable of picking out just the toxic aggregates while ignoring the benign forms. The Rensselaer researchers' antibody has also shown to be "more potent at preventing the aggregation of this toxic protein," notes Tessier. He calls the generality of their approach "another exciting aspect of it," adding that it has the potential to work for developing antibodies for other diseases as well since there are "several other aggregation disorders which are mediated by the same types of self-sticky interactions that lead to the formation of other types of particles."
"We're extending this approach now to other diseases, where we use the same design strategy now to try to target the toxic aggregates formed by other proteins linked to Parkinson's disease and related diseases," says Tessier.
Moving forward, the researchers will continue working to test the new design method in other diseases, and Tessier notes that they are also moving towards testing the Alzheimer's antibodies in cellular and animal models "to look at their effectiveness at preventing toxicity related to this Alzheimer's protein."
The Rensselaer team's discovery was detailed in the paper "Structure-based design of conformation- and sequence-specific antibodies against amyloid b," which was published in the Dec. 5 Early Edition of Proceedings of the National Academy of Sciences. The Alzheimer's Association, the National Science Foundation and the Pew Charitable Trust funded the research.