Making the best of a sticky situation

Rensselaer Polytechnic researchers discover new method for developing Alzheimer’s antibodies

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A new discovery at Rensselaer Polytechnic Institute couldhave far-reaching effects for patients suffering from Alzheimer's disease and otherdegenerative diseases, thanks to a team of researchers that has developed a new method todesign antibodies, specifically ones that can target the protein particles thatlead to Alzheimer's disease. Peter Tessier, Assistant Professor of Chemical andBiological Engineering, led the research. He was joined by three Rensselaergraduate students: Moumita Bhattacharya, Joseph Perchiacca and Ali RezaLadiwala, with the latter two holding the positions of co-first authors.
Antibodies are large proteins created by the immune systemin response to biological threats like infection or disease, and they consistof a Y-shaped protein topped with small peptide loops, which bind to thetargets they were created to fight. After the antibody has bonded to thetarget, the immune system sends cells to destroy the threat.
Currently, antibodies are generally made through a processcalled immunization. A molecule of interest is injected into the immune system,typically of animals, and "the immune system is able to select antibodies thatpresent the right combination of these peptide loops which have sequences inthem that would mediate binding to the molecule that you're interested in,"says Tessier. The antibody is then recovered from the animal's body, afterwhich it can be examined and reproduced. Though it obviously works, it is anextremely random process that offers very little control, Tessier notes.
"You're randomly varying these peptide loops and picking theneedle out of the haystack," he says.
The new method that the researchers discovered involvesusing the characteristics of the Alzheimer's protein against it. Alzheimer'sdisease is caused by the Alzheimer's proteins sticking together to form largerparticles. The particles, which are toxic to brain cells, damage the healthycells and brain functions as a result. According to Tessier, the Alzheimer'speptides that result from the proteins sticking together have regions withinthem that are self-complementary, with smaller segments that stick together inthe way that building blocks interlock. The researchers thought that they coulduse that feature to form an antibody that would naturally stick to the toxicparticles, and started with what Tessier called an antibody scaffold, a blankantibody form that is not designed to bind to anything.
"We actually took pieces of the sticky protein, theAlzheimer'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 thatthe sequence of these peptide loops could actually be literally a sequence fromthe target molecule that you're trying to bind to. And that was exactly ourhypothesis, that we could actually use the information about the targetmolecule, in this case the Alzheimer's protein, and literally graft—it's justlike grafting a branch into a tree—we grafted pieces of the Alzheimer's proteininto the antibody loop."
While other antibodies have been developed against theAlzheimer's protein, Tessier says that their antibody is unique in that ittargets only the toxic aggregates of the protein. Before it's aggregated, theAlzheimer's protein is soluble and not toxic, so the antibodies are capable ofpicking out just the toxic aggregates while ignoring the benign forms. TheRensselaer researchers' antibody has also shown to be "more potent atpreventing the aggregation of this toxic protein," notes Tessier. He calls thegenerality of their approach "another exciting aspect of it," adding that ithas the potential to work for developing antibodies for other diseases as wellsince there are "several other aggregation disorders which are mediated by thesame types of self-sticky interactions that lead to the formation of othertypes of particles."
"We're extending this approach now to other diseases, wherewe use the same design strategy now to try to target the toxic aggregatesformed by other proteins linked to Parkinson's disease and related diseases,"says Tessier.
Moving forward, the researchers will continue working to testthe new design method in other diseases, and Tessier notes that they are alsomoving towards testing the Alzheimer's antibodies in cellular and animal models"to look at their effectiveness at preventing toxicity related to thisAlzheimer's protein."
The Rensselaer team's discovery was detailed in the paper"Structure-based design of conformation- and sequence-specific antibodiesagainst amyloid b,"which was published in the Dec. 5 Early Edition of Proceedings of the National Academy of Sciences. The Alzheimer'sAssociation, the National Science Foundation and the Pew Charitable Trustfunded the research.

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