A synthetic peptide can inhibit the toxicity and aggregation of proteins in Alzheimer's disease



[ad_1]

Alzheimer's disease

PET-scan of a human brain with Alzheimer's disease. Credit: public domain

Alzheimer's disease is an aggregation disorder. Neurons in the human brain produce a protein called beta-amyloid. Such proteins, called beta-amyloid monomers, fulfill important tasks for neurons. But in the brains of people with Alzheimer's disease, amyloid beta-monomers have dropped out of work and have regrouped. First, they form oligomers – small mbades of a dozen proteins – then longer strands and finally large deposits called plates. For years, scientists have thought that plaques cause the cognitive impairments characteristic of Alzheimer's disease. But new research involves smaller aggregates of beta-amyloid as the toxic elements of this disease.

At present, a team led by researchers at the University of Washington has developed synthetic peptides that target and inhibit these small toxic aggregates. As they report in an article published the week of April 15 in the Proceedings of the National Academy of Sciencestheir synthetic peptides, designed to fold into a structure called alpha leaf, can block the early and most toxic beta-amyloid aggregation during oligomer formation.

The team showed that blocking activity of the synthetic alpha leaf reduced the toxicity triggered by amyloid beta in cultured human neural cells and inhibited beta-oligomers of amyloid in two Animal laboratory models for Alzheimer's disease. These findings add evidence to the growing consensus that amyloid beta-oligomers – and not plaques – are the toxic agents at the root of Alzheimer's disease. The results also indicate that synthetic alpha sheets could form the basis of the therapy to remove toxic oligomers in humans, according to the corresponding author, Valerie Daggett, professor of bioengineering at the UW and faculty member of the UW Molecular Engineering & Sciences Institute.

"It's about targeting a specific structure of beta-amyloid formed by toxic oligomers," said Daggett. "What we have shown here, is that we can design and build synthetic alpha sheets with complementary structures to inhibit the aggregation and toxicity of the beta-amyloid substance, while leaving intact the biologically active monomers. "

Cellular proteins take on many different 3D structures, usually by first folding into certain types of basic forms. The alpha sheet is a non-standard protein structure, discovered by Daggett's group using computer simulations. The research team has already shown that alpha leaves are badociated with beta-amyloid aggregation. These results, as well as the badociated results, indicate that, in nature, the alpha layers probably only occur in rare cases when the proteins fold incorrectly and interact in such a way as to disrupt cellular functioning, resulting in so-called diseases. of "protein folding" as Alzheimer's disease.

In this new article, Daggett and his team provide evidence that beta-amyloid oligomers form an alpha leaf structure when they aggregate into longer strands and plates. Critically, the team's synthetic alpha sheets can actually block this aggregation by specifically binding and neutralizing toxic oligomers.

Using both conventional and conventional spectroscopic techniques, Daggett's team observed the individual stages of development of beta-amyloid clusters, from monomers to oligomers to six and twelve proteins, through plaques, in human neural cell lines. The researchers confirmed that the oligomer stages were the most toxic for neurons, consistent with the clinical reports of amyloid beta-plaques in the brain of people without Alzheimer's disease.

"Beta-amyloid definitely plays a leading role in Alzheimer's disease, but even though, historically, attention has focused on plaques, more and more research indicates that Amyloid beta-oligomers are the toxic agents that disrupt neurons, "said Daggett.

In addition, the researchers designed and constructed small synthetic alpha sheet peptides, each made up of 23 amino acids, which are the basis of the proteins. Synthetic peptides folded in a hairpin structure and are not toxic to cells. But synthetic alpha leaves neutralized amyloid beta-oligomers in human neuronal cell cultures, inhibiting further aggregation by blocking portions of the oligomers involved in the formation of large clusters.

Peptides also protected laboratory animals from damage by toxic oligomers. In mouse brain tissue samples, the team observed a fall in levels of amyloid beta-oligomeric oligomers of up to 82% after treatment with a synthetic alpha-leaf peptide. The administration of a synthetic alpha leaf to live mice caused a 40% fall in amyloid beta-oligomer levels after 24 hours. In the common laboratory worm Caenorhabditis elegans, another model for Alzheimer's disease, treatment with synthetic alpha leaves delayed the onset of beta-amyloid-induced paralysis. In addition, C. elegans worms showed signs of intestinal lesions when they were fed with bacteria expressing beta-amyloid. This damage was inhibited when scientists treated bacteria for the first time with their synthetic alpha sheets.

The Daggett team continues its experiments with synthetic alpha sheets in order to develop even better compounds for the removal of amyloid beta-oligomers. For the present study, the researchers also created a new laboratory test using a synthetic alpha sheet to measure levels of amyloid beta-oligomers. They believe that this badysis could form the basis of a clinical test to detect toxic oligomers in people before the onset of Alzheimer's symptoms.

"What we are really looking for are potential treatments for beta-amyloid and diagnostic measures to detect toxic oligomers in humans," said Daggett. "These are the next steps."


Alzheimer's disease: is the cause completely wrong?


More information:
Dylan Shea et al., "The secondary structure of α leaf in β-amyloid peptide results in aggregation and toxicity in Alzheimer's disease" PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1820585116

Provided by
University of Washington


Quote:
A synthetic peptide can inhibit the toxicity and aggregation of proteins in Alzheimer's disease (April 15, 2019)
recovered on April 15, 2019
https://medicalxpress.com/news/2019-04-synthetic-peptide-inhibit-toxicity-aggregation.html

This document is subject to copyright. Apart from any fair use for study or private research purposes, no
part may be reproduced without written permission. Content is provided for information only.

[ad_2]
Source link