BY JAMIE TALAN
CHICAGO—Researchers have developed a strategy to prevent the formation of amyloid-beta (Abeta) with a compound that blocks the dimerization of the amyloid precursor protein (APP), according to a study described here on Monday at the annual meeting of the Society for Neuroscience.
Previous research has shown that inducing dimerization — the biochemical reaction that joins two molecules into a single dimer — increases Abeta, the researchers, led by Carmela R. Abraham, PhD, a professor of biochemistry and pharmacology at Boston University School of Medicine, and her colleagues explained in their abstract. In their study, they wanted to determine what would happen if they inhibited dimerization.
The findings, which build on research first published in 2012, could provide a new therapeutic target, said Dr. Abraham, whose colleague, Ella Zeldich, PhD, a post-doctoral fellow, presented the results at the meeting.
“There are a lot of companies working on inhibiting beta secretase and gamma secretase, the two enzymes that carve Abeta from its precursor, APP, or they are trying to clear the brain of Abeta using immunotherapy,” said Dr. Abraham. “I think it is important to stop Abeta from being made in the first place.”
She and her colleagues conducted a high-throughput screening of 77,140 small molecules — using 200 plates with 384 wells on each one — to determine if any of them could inhibit the dimerization of APP. They genetically engineered the APP molecules with firefly luciferase gene. When APP bound to another APP in the well, the two terminals of the firefly luciferase gene became luminescent. Then they added tens of thousands of different small molecules to each of the wells and waited to see which cells emitted light.
Only one substance in the panel, which they called Y, was able to stop the formation of a dimer between two APP molecules. The researchers observed that the substance was similar to other kinase inhibitors. When they tested the compound against select kinases, they found that it only inhibited a tyrosine kinase called cKit. And when they inhibited cKit, they observed an increase in the phosphorylation of APP and a decrease in Abeta.
“This is a whole pathway that has never been discovered that leads to the formation of Abeta,” said Dr. Abraham. “We don’t think that cKit directly induces the phosphorylation of APP, but the pathway definitely has a role in the cleavage of APP to generate Abeta.”
There are still many unanswered questions, including what needs to happen first, dimerization or phosphorylation. “We are not sure yet,” said Dr. Abraham. “But right now, what matters is that there is much less Abeta forming.”
Dennis J. Selkoe, MD, FAAN, the Vincent and Stella Coates professor of neurologic diseases at Harvard Medical School and Brigham and Women’s Hospital, said that the findings are quite interesting. “It is a novel mechanism that focuses on the dimerization of APP,” he said. “It is not known what percentage of APP forms dimers. But the key is to lower Abeta, which they have shown it does.”
Benjamin Wolozin, MD, PhD, a professor of pharmacology at Boston University added that “scientists now know how to get rid of Abeta using antibody approaches. The field has been looking beyond Abeta for new ways to treat Alzheimer’s. Still, people are not using phosphorylation to reduce Abeta. This definitely is a new approach that might impact the disease process.”
LINK UP FOR MORE INFORMATION:
· So PP, et al. Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid dimerization. Am J Neurodegener Dis 2012;1(1)75-87: http://1.usa.gov/1W3x1ej