To fight the development of neurodegenerative problems like Alzheimer’s illness and amyotrophic lateral sclerosis, scientists at Northwestern College and their collaborators have developed a way of trapping proteins earlier than they combination into poisonous buildings. Their strategy makes use of a category of peptide-based molecules known as amphiphiles and an extra ingredient—sugar, particularly trehalose.
Particulars of the tactic are printed within the Journal of the American Chemical Society in a paper titled, “Supramolecular copolymerization of glycopeptide amphiphiles and amyloid peptides improves neuron survival.” Outcomes reported within the paper present that the clean-up technique considerably boosted the survival of lab-grown human neurons that had been beneath stress from disease-causing proteins.
“Our research highlights the thrilling potential of molecularly engineered nanomaterials to deal with the foundation causes of neurodegenerative ailments,” mentioned Samuel Stupp, PhD, the research’s senior creator and founding director of Northwestern’s Heart for Regenerative Nanomedicine. “By trapping the misfolded proteins, our remedy inhibits the formation of these fibers at an early stage. Early stage, brief amyloid fibers, which penetrate neurons, are believed to be essentially the most poisonous buildings. With additional work, we expect this might considerably delay development of the illness.”
Peptide amphiphiles are already utilized in well-known prescription drugs, together with semaglutide, or Ozempic. For its half, trehalose is a naturally occurring sugar that’s present in vegetation, fungi, and bugs. It performs a task in defending them from altering temperatures, particularly dehydration and freezing.
“The benefit of peptide-based medicine is that they degrade into vitamins. The molecules on this novel therapeutic idea break down into innocent lipids, amino acids, and sugars. Meaning there are fewer opposed unwanted side effects,” mentioned Stupp. The addition of trehalose was primarily based on information from earlier research that present that “trehalose can defend many organic macromolecules, together with proteins. So, we wished to see if we might use it to stabilize misfolded proteins.”
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Their experiments confirmed that trehalose destabilizes the nanofibers, which really proves to be useful for trapping misfolded proteins. That’s as a result of by themselves, peptide amphiphile nanofibers are sturdy, well-ordered, and immune to structural modifications. Consequently, it’s tougher for different molecules, like misfolded proteins, to combine into the fibers. Much less secure fibers are extra dynamic and more likely to seek out and work together with poisonous proteins.
To get again to a place of stability, the nanofibers bonded to amyloid-beta proteins which might be attribute of Alzheimer’s illness, and prevented them from clumping. Moreover, the nanofibers absolutely included the proteins into their very own fibrous buildings, thus trapping them completely in secure filaments. The ultimate construction is “not a peptide amphiphile fiber anymore,” Stupp mentioned. “However a brand new hybrid construction comprising each the peptide amphiphile and the amyloid-beta protein. Meaning the nasty amyloid-beta proteins, which might have fashioned amyloid fibers, are trapped. They’ll not penetrate the neurons and kill them. It’s like a clean-up crew for misfolded proteins.”
To evaluate the therapeutic potential of the brand new strategy, Stupp and his staff examined the remedy in human neurons derived from stem cells. They discovered that the trehalose-coated nanofibers considerably improved the survival of each motor and cortical neurons when uncovered to the poisonous amyloid-beta protein.
Whereas there’s nonetheless extra work to do, this strategy affords a promising avenue for treating Alzheimer’s illness and different neurodegenerative circumstances, significantly together with different therapies. “Our remedy would possibly work finest when focusing on ailments at an earlier stage earlier than aggregated proteins enter cells,” Stupp mentioned. “However it’s difficult to diagnose these ailments at early levels. So, it might be mixed with therapies that focus on later-stage signs of the illness.”
