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 persistent¹ blood clots² that often form in the brains of Alzheimer's patients, contributing to the condition's hallmark memory loss, confusion and cognitive⁴ decline. New experiments in Sidney Strickland's Laboratory of Neurobiology and Genetics at Rockefeller University have identified a compound that might halt the progression of Alzheimer's by interfering⁵ with the role amyloid-β, a small protein that forms plaques⁶（斑块，瓷片） in Alzheimer's brains, plays in the formation of blood clots. This work is highlighted in the July issue of Nature Reviews Drug Discovery.

 

For more than a decade, potential Alzheimer's drugs have targeted amyloid-β, 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 bind⁷ to a clotting⁸ agent in blood, the work in the Strickland lab offers a promising⁹ new strategy, according to the highlight, which will be published in print on July 1.

 

This latest study builds on previous work in Strickland's lab showing amyloid-β can interact with fibrinogen（纤维蛋白原）, 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 cerebral¹⁰ 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 Journal of Experimental Medicine. Hyung Jin Ahn, a research associate in the lab, examined these candidates with a specific goal in mind: Find one that interferes¹¹ with the interaction between fibrinogen and amyloid-β. In a series of tests that began with a massive, automated¹³ screening effort at Rockefeller's High Throughput Resource Center, Ahn and colleagues winnowed¹⁴ the 93,000 contenders to five. Then, test tube experiments whittled¹⁵ the list down to one contender: RU-505, a small, synthetic¹⁶ compound. Because RU-505 binds¹⁷ to amyloid-β and only prevents abnormal blood clot³ formation, it does not interfere¹² with normal clotting. It is also capable of passing through the blood-brain barrier.

 

"We tested RU-505 in mouse models of Alzheimer's disease that over-express amyloid- β and have a relatively¹⁸ early onset¹⁹ of disease. Because Alzheimer's disease is a long-term, progressive disease, these treatments lasted for three months," Ahn says. "Afterward²⁰, we found evidence of improvement both at the cellular²¹ and the behavioral levels."

点击收听单词发音