Monday, April 22, 2019

Scientists develop synthetic peptide that could inhibit toxic aggregates in Alzheimer's disease


Researchers have developed synthetic peptides that could target and reduce toxic protein aggregates, which are supposed to cause Alzheimer's disease, a new study finds.


 Alzheimer's is a disease caused by the aggregation of the toxic protein. Neurons in the human brain make a protein called amyloid beta. Such proteins on their own, called monomers of amyloid beta, perform important tasks for neurons.

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But in the brains of people with Alzheimer's disease, amyloid beta monomers abandoned their jobs and get joined together. First, they form oligomers- small clusters of up to a dozen proteins- then longer strands and finally large deposits called plaques.

For years, scientists believed that plaques triggered the cognitive impairments characteristic of  Alzheimer's disease But newer research implicated the smaller aggregates of amyloid beta as the toxic elements of this disease.

The research reported that the synthetic peptides- which are designed to fold into a structure known as an alpha sheet- can block amyloid beta aggregation at the early and most toxic stage when oligomers form.

The team showed that the synthetic alpha sheet's blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer's.

These findings add evidence to the growing consensus that amyloid beta oligomers- not plaques- are the toxic agents behind Alzheimer's disease

The results also indicated that synthetic alpha sheets could form the basis of therapeutics to clear toxic oligomers in people, according to the author.

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

Using both novel and conventional spectroscopic techniques, the team observed the individual stages of development of amyloid beta clusters, from monomers to six- and 12-protein oligomers all the way up to plaques, in human neural cell lines.

The researchers confirmed that the oligomer stages were most toxic to the neurons, which agrees with clinical reports of amyloid beta plaques in the brains of people who don't have Alzheimer's.

"Amyloid beta 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," he said.

The synthetic alpha sheet also protected laboratory animals from toxic oligomer damage. In brain tissue samples from mice, the team observed an up to 82 per cent drop in amyloid beta oligomer levels after treatment with a synthetic alpha sheet peptide

Administering a synthetic alpha sheet to living mice triggered a 40 per cent drop in amyloid beta oligomer levels after 24 hours.

In the common laboratory worm Caenorhabditis elegans (C. elegans), another model for Alzheimer's disease, treatment with synthetic alpha sheets delayed the onset of  amyloid-beta-induced paralysis.

For the current study, the researchers also created a novel laboratory assay that uses a synthetic alpha sheet to measure levels of amyloid beta oligomers. They believe this assay 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 after are potential therapeutics against amyloid beta and diagnostic measures to detect toxic oligomers in people. Those are the next steps," he said.

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Saturday, December 27, 2014

Researchers discover new non-invasive method can detect Alzheimer's early

Researchers, including those of Indian origin, have developed a noninvasive method that can detect Alzheimer's disease in a living animal, well before typical symptoms appear.

An interdisciplinary team of Northwestern University scientists and engineers have developed a noninvasive MRI (magnetic resonance imaging) probe that pairs a magnetic nanostructure (MNS) with an antibody that seeks out the amyloid beta brain toxins responsible for onset of Alzheimer's disease.

The accumulated toxins, because of the associated magnetic nanostructures, show up as dark areas in MRI scans of the brain. "We have a new brain imaging method that can detect the toxin that leads to Alzheimer's disease," said neuroscientist William L Klein who led the research team along with materials scientist Vinayak P Dravid. "Using MRI, we can see the toxins attached to neurons in the brain. We expect to use this tool to detect this disease early and to help identify drugs that can effectively eliminate the toxin and improve health," Klein said.

The new MRI probe technology is detecting something different from conventional technology: toxic amyloid beta oligomers instead of plaques, which occur at a stage of Alzheimer's when therapeutic intervention would be very late. Amyloid beta oligomers now are widely believed to be the culprit in the onset of Alzheimer's disease and subsequent memory loss.

In a diseased brain, the mobile amyloid beta oligomers attack the synapses of neurons, destroying memory and ultimately resulting in neuron death. As time progresses, the amyloid beta builds up and starts to stick together, forming the amyloid plaques that current probes target. Oligomers may appear more than a decade before plaques are detected.

"Non-invasive imaging by MRI of amyloid beta oligomers is a giant step forward towards diagnosis of this debilitating disease in its earliest form," said Dravid, the Abraham Harris Professor of Materials Science and Engineering at the McCormick School of Engineering and Applied Science. "This MRI method could be used to determine how well a new drug is working. If a drug is effective, you would expect the amyloid beta signal to go down," Dravid said.

The nontoxic MRI probe was delivered intranasally to mouse models with Alzheimer's disease and control animals without the disease. In animals with Alzheimer's, the toxins' presence can be seen clearly in the hippocampus in MRI scans of the brain. No dark areas, however, were seen in the hippocampus of the control group.

Researchers Ruchi Sureka, Mrinmoy De, Shaleen Vasavada, Sreyesh Satpathy, Summer Wu, Hrushikesh Joshi and Pottumarthi Prasad also worked on the study published in the journal Nature Nanotechnology.

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