According to the World Health Organization, as many as 50 million people worldwide might have a neurodegenerative disorder. Most of these diseases are characterized by the accumulation of misfolded proteins in the brain, leading to the progressive loss of neurons. While current treatments offer limited relief, a dire need for new therapies remains.
In many neurodegenerative diseases, proteins misfold and clump together in brain tissue. As part of searchers for treatment, scientists have developed a new therapy made of peptides and a sugar that naturally occurs in plants. This new treatment traps, neutralizes toxic proteins to stop Alzheimer’s disease progression.
The therapeutic molecules self-assemble into nanofibers, which bond to the neuron-killing proteins. Now trapped, the toxic proteins can no longer enter neurons and instead harmlessly degrade.
Molecularly engineered nanomaterials
In these devastating illnesses, proteins misfold and clump together around brain cells, which ultimately leads to cell death. The innovative new treatment effectively traps the proteins before they can aggregate into the toxic structures capable of penetrating neurons. The trapped proteins then harmlessly degrade in the body.
The “clean-up” strategy significantly boosted the survival of lab-grown human neurons under stress from disease-causing proteins.
According to Northwestern’s Samuel I. Stupp: “Our study highlights the exciting potential of molecularly engineered nanomaterials to address the root causes of neurodegenerative diseases. In many of these diseases, proteins lose their functional folded structure and aggregate to make destructive fibres that enter neurons and are highly toxic to them.”
Stupp continues: “By trapping the misfolded proteins, our treatment inhibits the formation of those fibres at an early stage. Early stage, short amyloid fibres, which penetrate neurons, are believed to be the most toxic structures. With further work, we think this could significantly delay progression of the disease.”
A sugar-coated solution
The researchers turned to a class of peptide amphiphiles, pioneered by the Stupp laboratory, that contain modified chains of amino acids. Peptide amphiphiles are already used in well-known pharmaceuticals including semaglutide, or Ozempic.
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.
Instability is key
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Surprisingly, the trehalose destabilized the nanofibers. Although it seems counterintuitive, this decreased stability exhibited a beneficial effect.
By themselves, the nanofibers are strong and well-ordered — and resistant to rearranging their structure. That makes it more difficult for other molecules, like misfolded proteins, to integrate into the fibres. Less stable fibres, on the other hand, became more dynamic — and more likely to find and interact with toxic proteins.
Searching for stability, the nanofibers bonded to amyloid-beta proteins, a key culprit implicated in Alzheimer’s disease. But the nanofibers didn’t just stop the amyloid-beta proteins from clumping together. The nanofibers fully incorporated the proteins into their own fibrous structures — permanently trapping them into stable filaments.
“Then, it’s no longer a peptide amphiphile fibre anymore,” Stupp indicates. “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.”
He concludes: “This is a novel mechanism to tackle progression of neurodegenerative diseases, such as Alzheimer’s, at an earlier stage. Current therapies rely on the production of antibodies for well-formed amyloid fibres.”
The scientists conducted laboratory tests using human neurons derived from stem cells. The results showed the trehalose-coated nanofibers significantly improved the survival of both motor and cortical neurons when exposed to the toxic amyloid-beta protein. This offers a promising avenue for developing new and effective therapies for Alzheimer’s, ALS and other neurodegenerative conditions.
Research paper
The research has been published in the Journal of the American Chemical Society. The paper is titled: “Supramolecular copolymerization of glycopeptide amphiphiles and amyloid peptides improves neuron survival”.
