View of Alzheimer’s Disease Peptide Could Inform New Drugs

Over the last couple of years, the U.S. Food and Drug Administration (FDA) has approved two therapies that reduce the amount of amyloid beta in the brain, but their benefits are limited, and they can cause severe side effects. The findings could inform new therapies that target the harmful forms of amyloid beta while preserving non-pathogenic forms, the scientists say.

“This intermediate state—the ‘oligomeric’ state—is the one that’s likely actually causing the damage to the brain, but we haven’t known exactly what it is, and therefore we haven’t been able to figure out the best way to target it with drugs in a specific manner,” says Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology, chair of the Department of Neuroscience at Yale School of Medicine, and the study’s principal investigator.

Over the last decade, Strittmatter’s team has been studying the receptors on neurons that interact with “oligomeric” amyloid beta. Through this work, they have discovered that those receptors bind very tightly to the peptides. As a result, scientists have struggled to characterize the structure of oligomeric amyloid beta because the peptides are difficult to remove from these receptors and there’s very little non-bound oligomeric amyloid beta in the brain.

To overcome this challenge, Strittmatter’s team treated human brain tissue affected by Alzheimer’s disease with a drug that could displace “oligomeric” amyloid beta from receptors. Then, they purified the toxic peptide from its other forms. When the researchers took the purified oligomeric peptides and added it to cultured human neurons, the cells became damaged, proving that they were still biologically active.

Then, they used several microscopy methods to visualize the structure of the peptide. Unlike plaque amyloid beta, which exists as long filaments thousands of nanometers long, “oligomeric” amyloid beta is composed of short rods of about 65 nanometers. While similar in structure to plaques, they identified key differences in the ways groups of atoms were arranged. Thus, the toxic receptor-bound “oligomers” were in fact short filaments different from the plaque amyloid beta.

“They have a unique, distinct structure,” Strittmatter says.

They also discovered that “oligomeric” amyloid beta could stimulate the formation of more toxic peptides. “Polymerization is biased against long filaments,” Strittmatter says.

In 2023, the FDA approved lecanemab (Leqembi) as the first anti-amyloid beta therapy for the treatment of Alzheimer’s disease. The following year, they approved a second drug named donanemab (Kisunla). However, these drugs only slow the disease by about 30% and can cause serious side effects including inflammation and bleeding in the brain. These antibodies target both the plaque amyloid beta and the “oligomeric” amyloid beta, but their toxicities likely result from clearance of the plaque form.

By understanding the structural differences between different subsets of amyloid beta, scientists may develop better drugs that specifically target the harmful intermediate form.

“Now that we have atomic resolution on the bad stuff in the Alzheimer’s brain, we hope that will lead to new ways to treat the disease,” Strittmatter says.

Source: Yale University