Alzheimer’s: Synthetic protein blocks toxic beta-amyloid

The synthetic peptide, which has only 23 amino acids, folds into structures called alpha sheets. The sheets bind to early-stage, small clumps of beta-amyloid and stop them forming larger masses.

A team from the University of Washington (UW) in Seattle and other research centers in the United States designed and produced the synthetic peptide and also tested it in cells and animals.

The tests showed that alpha sheets of the peptide reduced the toxic impact of beta-amyloid in cultured human brain cells. The sheets also blocked early forms of beta-amyloid in animal models of Alzheimer’s disease.

The Proceedings of the National Academy of Sciences is shortly to feature a paper about the study.

The researchers say that the findings could lead to treatments that clear away toxic beta-amyloid in its early forms. They also see potential for using the peptide as the basis of a test for diagnosing Alzheimer’s disease before symptoms emerge.

Toxic beta-amyloid is a distinguishing hallmark of Alzheimer’s disease. But not all forms of beta-amyloid are toxic. Brain cells, or neurons, make the protein in a simple form called a monomer. Monomer forms of beta-amyloid carry out essential jobs in brains cells.

However, in people with Alzheimer’s disease, beta-amyloid monomers cluster into oligomers, which can contain up to 12 monomers.

In Alzheimer’s disease, the oligomers continue to grow into longer shapes, and then eventually, they form much bigger deposits, or plaques.

At first, scientists thought that plaques were the most toxic form of beta-amyloid that produced symptoms of Alzheimer’s disease, such as loss of memory and thinking capacity.

However, due to growing evidence, an increasing number of experts are suggesting that the earlier oligomer stages of beta-amyloid are likely to be the most toxic to brain cells.

Synthetic peptide targets oligomers

The researchers designed the synthetic peptide alpha sheets to target beta-amyloid while it is at the oligomer-forming stage.

“This is,” says corresponding study author Valerie Daggett, who is a professor of bioengineering at UW, “about targeting a specific structure of [beta-amyloid] formed by the toxic oligomers.”

The study shows, she adds, that it is possible to devise synthetic peptide alpha sheets whose structures “complement” those of beta-amyloid as it assumes a toxic form, “while leaving the biologically active monomers intact.”

The process of making proteins in cells eventually produces molecules of diverse 3D shapes. The first stage of this involves folding the long chain into one of several basic shapes.

Prof. Daggett’s team had discovered one such basic shape — the alpha sheet — in earlier work in which they had simulated production of proteins on computers.

The recent study reveals that beta-amyloid oligomers adopt the alpha-sheet shape as they form longer clumps and plaques.

It also shows that the synthetic peptide alpha sheet binds only to beta-amyloid oligomer alpha sheets and that this neutralizes their toxicity.

The team used traditional and state-of-the-art spectroscopes to watch how beta-amyloid progressed from monomers to oligomers to plaques in cultured human brain cells.

They also confirmed that oligomers were more harmful to brain cells than plaques. This finding supports studies that have found beta-amyloid plaques in the brains of people without Alzheimer’s disease.

The team showed that treating samples of brain tissue from a mouse model of Alzheimer’s disease with alpha sheets of synthetic peptide led to an 82 percent reduction in beta-amyloid oligomers.

In addition, treating the live mice with alpha sheets of synthetic peptide reduced their beta-amyloid oligomer levels by 40 percent within 24 hours.

The team also carried out experiments on another common model of Alzheimer’s disease, the worm Caenorhabditis elegans. These showed that treatment with alpha sheets of synthetic peptide was able to delay paralysis due to beta-amyloid.

Finally, the researchers showed that it could be possible to use alpha sheets of synthetic peptide to test for levels of beta-amyloid oligomers.

Prof. Daggett and her team are already experimenting with new versions of synthetic peptide alpha sheets to find those that can neutralize beta-amyloid oligomers even more effectively.

“[Beta-amyloid] definitely plays a lead role in Alzheimer’s disease, but while historically attention has been on the plaques, more and more research instead indicates that amyloid beta oligomers are the toxic agents that disrupt neurons.”

Professor Valerie Daggett