Inhibiting Formation of Amyloid Oligomers as a Strategy to Slow Alzheimer's Disease

Finding ways to inhibit the formation of toxic amyloid-β oligomers in the aging brain may prove to be a useful treatment for Alzheimer's disease, but it remains the case that therapies targeting amyloid-β have yet to show meaningful patient benefits. It is possible that the wrong type or location of amyloid-β was targeted, or that amyloid-β is not directly responsible for Alzheimer's disease, but rather a side-effect of other disease processes. Regardless, a great deal of effort still goes into targeting aspects of amyloid-β biochemistry, in the hopes that one of these approaches will succeed where past efforts have failed.

Because plaques are visible under a microscope, scientists long believed that they are responsible for damaging neurons in Alzheimer's disease etiology. Many clinical trials took place and billions in funding were invested over more than a quarter of a century to generate molecules and antibodies targeting and preventing formation of fibrils and plaques. Such treatments proved unsuccessful and caused intolerable side effects. Over time, fibrils and plaques themselves were deemed non-toxic, and instead earlier soluble intermediates known as oligomers are now considered the culprits in this insidious disease.

Recent clinical trials using antibodies to target oligomers have shown promising results. Researchers are now developing small cyclic peptides that have proven effective in animal models in treating the disease by targeting oligomers. When these molecules were combined in a test tube with the small protein amyloid beta, the generation of oligomers was completely blocked, and no subsequent aggregation occurred. In the next stage, the researchers incubated human neurons with the toxic oligomers and the cyclic peptides. Most neurons remained alive, but those in the control group that were exposed to the oligomers without cyclic peptides were severely damaged and died.

Next, transgenic mouse models of Alzheimer's disease in the pre-symptomatic stage were treated with the cyclic peptides and observed over time for memory functions and amount of amyloid beta oligomers in the brain. Through molecular imaging, the researchers determined that the mice didn't generate substantial amounts of oligomers and, consequently, didn't develop any sign of Alzheimer's.