Scientists at Northwestern University have developed a new approach that directly combats the progression of neurodegenerative diseases such as Alzheimer’s and amyotrophic lateral sclerosis (ALS). In these devastating diseases, proteins misfold and clump together around brain cells, ultimately leading to cell death. The innovative new treatment effectively traps the proteins before they can aggregate into toxic structures that invade the nerve cells. The captured proteins are then harmlessly degraded in the body. The “cleaning strategy” significantly improved the survival rate of lab-grown human neurons under stress from disease-causing proteins. The study was selected as an “ACS Editor’s Choice” and published in the Journal of the American Chemical Society.
Possibility to Delay the Progression of Alzheimer’s Disease
“Our study highlights the exciting potential of molecularly engineered nanomaterials to address the causes of neurodegenerative diseases,” said Samuel I. Stupp of Northwestern University, lead author of the study. “In many of these diseases, proteins lose their functional folded structure and aggregate into destructive fibers that penetrate neurons and become highly toxic. By trapping the misfolded proteins, our treatment inhibits the formation of these fibers at an early stage. It is believed that short, early-stage amyloid fibers that enter neurons are the most toxic structures. We believe that with further research this could significantly delay the progression of the disease.”
Stupp is a pioneer in regenerative medicine and a professor of materials science and engineering, chemistry, medicine and biomedical engineering at Northwestern University, where he is on the faculty of the McCormick School of Engineering, the Weinberg College of Arts and Sciences and the Feinberg School of Medicine. He is also the founding director of the Center for Regenerative Nanomedicine (CRN). Zijun Gao, a graduate student in Stupp’s lab, is the first author of the paper. The Stupp group led the development and characterization of the new therapeutic materials. Co-author Zaida Alvarez – a researcher at the Institute of Bioengineering of Catalonia (IBEC) in Spain, former postdoctoral researcher in Stupp’s lab and currently a visiting scientist at the CRN – led the testing of the therapies on human neurons.
A Sugar-Coated Solution
According to the World Health Organization, up to 50 million people worldwide suffer from a neurodegenerative disease. Most of these diseases are characterized by the accumulation of misfolded proteins in the brain that lead to the progressive loss of nerve cells. Current treatment options offer only limited relief, so there is an urgent need for new therapies. To address this challenge, researchers turned to a class of peptidic amphiphiles developed by the Stupp lab that contain modified amino acid chains. Peptidic amphiphiles are already used in well-known drugs such as semaglutide or Ozempic. In fact, researchers at Northwestern University developed a similar molecule back in 2012 that increased insulin production.
Over the years, Stupp’s research group has developed many peptide-based materials for various therapeutic purposes. To develop an amphiphilic peptide to treat neurodegenerative diseases, his team added an additional ingredient: a natural sugar called trehalose. “Trehalose occurs naturally in plants, fungi and insects,” says Gao. It protects them from temperature fluctuations, especially from dehydration and frostbite. Other researchers have discovered that trehalose can protect many biological macromolecules, including proteins. The experts therefore wanted to find out whether they could use these to stabilize misfolded proteins.
Novel Mechanism Helps to Counteract Neurodegenerative Diseases Such as Alzheimer’s at an Earlier Stage
When added to water, the amphiphilic peptides independently formed nanofibers coated with trehalose. Surprisingly, the trehalose destabilized the nanofibers. Although this seems counterintuitive, this reduced stability had a positive effect. On their own, the nanofibers are strong and well-ordered – and resistant to structural rearrangements. This makes it more difficult for other molecules, such as misfolded proteins, to integrate into the fibers. Less stable fibers, on the other hand, became more dynamic – and found toxic proteins with which they could interact more easily. In their search for stability, the nanofibers bonded with amyloid beta proteins, an important trigger of Alzheimer’s disease. But the nanofibers didn’t just prevent the amyloid beta proteins from clumping together. The nanofibers completely incorporated the proteins into their own fiber structures and thus permanently enclosed them in stable filaments.
“It is then no longer an amphiphilic peptide fiber. Instead, it is a new hybrid structure that contains both the amphiphilic peptide and the amyloid beta protein” , says Stupp. “This means that the harmful amyloid beta proteins, which would have formed amyloid fibers, are enclosed. They can no longer penetrate the neurons and kill them. It’s like a cleaning squad for misfolded proteins. This is a novel mechanism to counteract neurodegenerative diseases such as Alzheimer’s at an earlier stage. Current therapies are based on the production of antibodies against well-formed amyloid fibers.”
Development of Innovative and Effective Therapies
To evaluate the therapeutic potential of the new approach, the scientists conducted laboratory tests with human neurons derived from stem cells. The results showed that the trehalose-coated nanofibers significantly improved the survival of both motor and cortical neurons when exposed to the toxic amyloid beta protein.
Stupp says the novel approach of using unstable nanofibers to trap proteins represents a promising avenue for the development of new and effective therapies for Alzheimer’s, ALS and other neurodegenerative diseases. Similar to cancer treatments that combine multiple therapies – such as chemotherapy and surgery or hormone therapy and radiation – nanotherapy could be most effective when combined with other treatments, according to Stupp. It could then achieve a double effect