Evanston, IL — A groundbreaking study from Northwestern University presents a promising new therapeutic strategy targeting the progression of neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). The innovative approach directly addresses a core issue in these illnesses: the harmful buildup of misfolded proteins in the brain.
Neurodegenerative diseases like Alzheimer’s and ALS are marked by the misfolding and accumulation of proteins around brain cells, leading to neuronal death. The new Northwestern method works by trapping these misfolded proteins before they clump into toxic structures capable of damaging neurons. Once captured, the proteins degrade harmlessly in the body, offering a potential breakthrough in early-stage intervention.
The study, titled “Supramolecular copolymerization of glycopeptide amphiphiles and amyloid peptides improves neuron survival,” will be published May 14 in the Journal of the American Chemical Society and has been designated an ACS Editor’s Choice article.
“Our study highlights the exciting potential of molecularly engineered nanomaterials to address the root causes of neurodegenerative diseases,” said Dr. Samuel I. Stupp, senior author of the study and Board of Trustees Professor at Northwestern. “By trapping misfolded proteins, our treatment inhibits the formation of toxic amyloid fibers at an early stage.”
The new therapy is built on peptide amphiphiles—molecules developed by the Stupp laboratory—known for their applications in various pharmaceutical treatments, including the popular diabetes drug semaglutide (Ozempic). Peptide-based drugs have the added advantage of biodegrading into non-toxic components such as amino acids, lipids, and sugars, reducing the risk of adverse side effects.
To enhance the treatment, Stupp’s team added trehalose, a naturally occurring sugar found in plants, fungi, and insects. Trehalose has known properties that stabilize proteins and protect biological structures from environmental stress. When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose.
However, the sugar’s inclusion destabilized the nanofibers—a seemingly counterintuitive but ultimately beneficial result. The less stable, more dynamic nanofibers actively sought interactions with misfolded proteins, making them ideal for capturing toxic amyloid-beta, a key protein implicated in Alzheimer’s disease.
“Unstable assemblies of molecules are very reactive,” said Stupp. “If the nanofibers were stable, they would happily ignore everything around them. But in their unstable form, they bind to amyloid proteins and neutralize them.”
The captured amyloid-beta proteins are fully integrated into the nanofibers, forming a new, stable hybrid structure. In this state, they are unable to form toxic fibers or penetrate neurons, effectively halting the cell damage that drives disease progression.
To evaluate the treatment’s efficacy, the research team conducted experiments using human neurons derived from stem cells. The results were compelling: motor and cortical neurons exposed to toxic amyloid-beta proteins had significantly improved survival rates when treated with the trehalose-coated nanofibers.
“This is a novel mechanism to tackle neurodegenerative diseases at an earlier stage,” Stupp explained. “Current therapies depend on antibodies that target fully formed amyloid fibers, but we’re aiming to intervene before those even develop.”
The research was led by Zijun Gao, a Ph.D. candidate in Stupp’s lab and first author of the paper. Co-corresponding author Zaida Alvarez, now a researcher at the Institute for Bioengineering of Catalonia (IBEC) in Spain and a visiting scholar at Northwestern’s Center for Regenerative Nanomedicine, oversaw the human neuron testing phase.
According to the World Health Organization, approximately 50 million people worldwide are affected by neurodegenerative disorders. While existing treatments provide limited symptom relief, no current therapy offers a robust method to halt disease progression—especially in the early stages.
Stupp believes this nanotherapy could form part of a combined treatment strategy, much like how cancer therapies often integrate chemotherapy, radiation, and surgery.
“Our therapy might work best when targeting diseases at an earlier stage—before aggregated proteins enter cells,” Stupp said. “But since early diagnosis is difficult, combining it with treatments for later-stage symptoms could be even more effective. It could be a double whammy.”
The study was supported by a network of institutions and funding sources, including the Center for Regenerative Nanomedicine, the Chemistry of Life Processes Institute, the Spanish Ministry of Science, the National Institute on Aging of the National Institutes of Health, and the European Union’s NextGenerationEU initiative.
As researchers continue to refine the approach, the therapy offers a hopeful new path in the fight against some of the most debilitating neurological diseases of our time.
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