Potential Alzheimer's Drug Prevents Abnormal Blood Clots In The Brain
Without a steady supply of blood, neurons can’t work. That’s why one of the culprits behind Alzheimer’s disease is believed to be the persistent blood clots that often form in the brains of Alzheimer’s patients, contributing to the condition’s hallmark memory loss, confusion and cognitive decline.
New experiments in Sidney Strickland’s
For more than a decade, potential Alzheimer’s drugs have targeted amyloid-ß, but, in clinical trials, they have either failed to slow the progression of the disease or caused serious side effects. However, by targeting the protein’s ability to bind to a clotting agent in blood, the work in the Strickland lab offers a promising new strategy, according to the highlight, which will be published in print on
This latest study builds on previous work in Strickland’s lab showing amyloid-ß can interact with fibrinogen, the clotting agent, to form difficult-to-break-down clots that alter blood flow, cause inflammation and choke neurons.
“Our experiments in test tubes and in mouse models of Alzheimer’s showed the compound, known as RU-505, helped restore normal clotting and cerebral blood flow. But the big pay-off came with behavioral tests in which the Alzheimer’s mice treated with RU-505 exhibited better memories than their untreated counterparts,” Strickland says. “These results suggest we have found a new strategy with which to treat Alzheimer’s disease.”
RU-505 emerged from a pack of 93,716 candidates selected from libraries of compounds, the researchers write in the June issue of the
“We tested RU-505 in mouse models of Alzheimer’s disease that over-express amyloid- ß and have a relatively early onset of disease. Because Alzheimer’s disease is a long-term, progressive disease, these treatments lasted for three months,” Ahn says. “Afterward, we found evidence of improvement both at the cellular and the behavioral levels.”
The brains of the treated mice had less of the chronic and harmful inflammation associated with the disease, and blood flow in their brains was closer to normal than that of untreated Alzheimer’s mice. The RU-505-treated mice also did better when placed in a maze. Mice naturally want to escape the maze, and are trained to recognize visual cues to find the exit quickly. Even after training, Alzheimer’s mice have difficulty in exiting the maze. After these mice were treated with RU-505, they performed much better.
“While the behavior and the brains of the Alzheimer’s mice did not fully recover, the three-month treatment with RU-505 prevents much of the decline associated with the disease,” Strickland says.
The researchers have begun the next steps toward developing a human treatment. Refinements to the compound are being supported by the
“At very high doses, RU-505 is toxic to mice and even at lower doses it caused some inflammation at the injection site, so we are hoping to find ways to reduce this toxicity, while also increasing RU-505's efficacy so smaller doses can accomplish similar results,” Ahn says.
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