To combat the progression of neurodegenerative disorders like Alzheimer’s disease and amyotrophic lateral sclerosis, scientists at Northwestern University and their collaborators have developed a method of trapping proteins before they aggregate into toxic structures. Their approach uses a class of peptide-based molecules called amphiphiles and an additional ingredient—sugar, specifically trehalose.
Details of the method are published in the Journal of the American Chemical Society in a paper titled, “Supramolecular copolymerization of glycopeptide amphiphiles and amyloid peptides improves neuron survival.” Results reported in the paper show that the clean-up strategy significantly boosted the survival of lab-grown human neurons that were under stress from disease-causing proteins.
“Our study highlights the exciting potential of molecularly engineered nanomaterials to address the root causes of neurodegenerative diseases,” said Samuel Stupp, PhD, the study’s senior author and founding director of Northwestern’s Center for Regenerative Nanomedicine. “By trapping the misfolded proteins, our treatment inhibits the formation of those fibers at an early stage. Early stage, short amyloid fibers, which penetrate neurons, are believed to be the most toxic structures. With further work, we think this could significantly delay progression of the disease.”
Peptide amphiphiles are already used in well-known pharmaceuticals, including semaglutide, or Ozempic. For its part, trehalose is a naturally occurring sugar that is found in plants, fungi, and insects. It plays a role in protecting them from changing temperatures, especially dehydration and freezing.
“The advantage of peptide-based drugs is that they degrade into nutrients. The molecules in this novel therapeutic concept break down into harmless lipids, amino acids, and sugars. That means there are fewer adverse side effects,” said Stupp. The addition of trehalose was based on data from previous studies that show that “trehalose can protect many biological macromolecules, including proteins. So, we wanted to see if we could use it to stabilize misfolded proteins.”
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Their experiments showed that trehalose destabilizes the nanofibers, which actually proves to be beneficial for trapping misfolded proteins. That’s because by themselves, peptide amphiphile nanofibers are strong, well-ordered, and resistant to structural changes. As a result, it is more difficult for other molecules, like misfolded proteins, to integrate into the fibers. Less stable fibers are more dynamic and much more likely to find and interact with toxic proteins.
To get back to a position of stability, the nanofibers bonded to amyloid-beta proteins that are characteristic of Alzheimer’s disease, and prevented them from clumping. Furthermore, the nanofibers fully incorporated the proteins into their own fibrous structures, thus trapping them permanently in stable filaments. The final structure is “no longer a peptide amphiphile fiber anymore,” Stupp said. “But a new hybrid structure comprising both the peptide amphiphile and the amyloid-beta protein. That means the nasty amyloid-beta proteins, which would have formed amyloid fibers, are trapped. They can no longer penetrate the neurons and kill them. It’s like a clean-up crew for misfolded proteins.”
To assess the therapeutic potential of the new approach, Stupp and his team tested the treatment in human neurons derived from stem cells. They found that the trehalose-coated nanofibers significantly improved the survival of both motor and cortical neurons when exposed to the toxic amyloid-beta protein.
While there is still more work to do, this approach offers a promising avenue for treating Alzheimer’s disease and other neurodegenerative conditions, particularly in combination with other treatments. “Our therapy might work best when targeting diseases at an earlier stage before aggregated proteins enter cells,” Stupp said. “But it’s challenging to diagnose these diseases at early stages. So, it could be combined with therapies that target later-stage symptoms of the disease.”
The post Sweet Solution: Sugar-Coated Nanotherapy Halts Alzheimer’s Disease by Trapping Toxic Proteins appeared first on GEN - Genetic Engineering and Biotechnology News.
Details of the method are published in the Journal of the American Chemical Society in a paper titled, “Supramolecular copolymerization of glycopeptide amphiphiles and amyloid peptides improves neuron survival.” Results reported in the paper show that the clean-up strategy significantly boosted the survival of lab-grown human neurons that were under stress from disease-causing proteins.
“Our study highlights the exciting potential of molecularly engineered nanomaterials to address the root causes of neurodegenerative diseases,” said Samuel Stupp, PhD, the study’s senior author and founding director of Northwestern’s Center for Regenerative Nanomedicine. “By trapping the misfolded proteins, our treatment inhibits the formation of those fibers at an early stage. Early stage, short amyloid fibers, which penetrate neurons, are believed to be the most toxic structures. With further work, we think this could significantly delay progression of the disease.”
Peptide amphiphiles are already used in well-known pharmaceuticals, including semaglutide, or Ozempic. For its part, trehalose is a naturally occurring sugar that is found in plants, fungi, and insects. It plays a role in protecting them from changing temperatures, especially dehydration and freezing.
“The advantage of peptide-based drugs is that they degrade into nutrients. The molecules in this novel therapeutic concept break down into harmless lipids, amino acids, and sugars. That means there are fewer adverse side effects,” said Stupp. The addition of trehalose was based on data from previous studies that show that “trehalose can protect many biological macromolecules, including proteins. So, we wanted to see if we could use it to stabilize misfolded proteins.”
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Their experiments showed that trehalose destabilizes the nanofibers, which actually proves to be beneficial for trapping misfolded proteins. That’s because by themselves, peptide amphiphile nanofibers are strong, well-ordered, and resistant to structural changes. As a result, it is more difficult for other molecules, like misfolded proteins, to integrate into the fibers. Less stable fibers are more dynamic and much more likely to find and interact with toxic proteins.
To get back to a position of stability, the nanofibers bonded to amyloid-beta proteins that are characteristic of Alzheimer’s disease, and prevented them from clumping. Furthermore, the nanofibers fully incorporated the proteins into their own fibrous structures, thus trapping them permanently in stable filaments. The final structure is “no longer a peptide amphiphile fiber anymore,” Stupp said. “But a new hybrid structure comprising both the peptide amphiphile and the amyloid-beta protein. That means the nasty amyloid-beta proteins, which would have formed amyloid fibers, are trapped. They can no longer penetrate the neurons and kill them. It’s like a clean-up crew for misfolded proteins.”
To assess the therapeutic potential of the new approach, Stupp and his team tested the treatment in human neurons derived from stem cells. They found that the trehalose-coated nanofibers significantly improved the survival of both motor and cortical neurons when exposed to the toxic amyloid-beta protein.
While there is still more work to do, this approach offers a promising avenue for treating Alzheimer’s disease and other neurodegenerative conditions, particularly in combination with other treatments. “Our therapy might work best when targeting diseases at an earlier stage before aggregated proteins enter cells,” Stupp said. “But it’s challenging to diagnose these diseases at early stages. So, it could be combined with therapies that target later-stage symptoms of the disease.”
The post Sweet Solution: Sugar-Coated Nanotherapy Halts Alzheimer’s Disease by Trapping Toxic Proteins appeared first on GEN - Genetic Engineering and Biotechnology News.