A Cleanup Crew for the Brain

Neurodegenerative disorders affect up to 50 million people worldwide, according to the World Health Organization. In diseases such as Alzheimer’s and ALS, proteins misfold and clump together in structures around brain cells. The accumulation of misfolded proteins ultimately leads to cell death and the progressive loss of neurons. While current treatments offer limited relief, a dire need for new therapies remains.  

Northwestern scientists have developed a therapy that combats the progression of neurodegenerative diseases by effectively trapping the proteins before they can aggregate into the toxic structures capable of penetrating neurons.  

Made of peptides — short chains of amino acids — and a naturally occurring sugar, the therapeutic molecules self-assemble into nanofibers, which bond to the neuron-killing proteins. The trapped proteins then harmlessly degrade in the body. 

“Our study highlights the exciting potential of molecularly engineered nanomaterials to address the root causes of neurodegenerative diseases,” says Samuel I. Stupp ’77 PhD. “In many of these diseases, proteins lose their functional folded structure and aggregate to make destructive fibers that enter neurons and are highly toxic to them. 

“By trapping the misfolded proteins, our treatment inhibits the formation of those fibers. 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.” 

To tackle this challenge, the researchers used 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. 

“The advantage of peptide-based drugs is that they degrade into nutrients,” says Stupp, the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering. “The molecules in this novel therapeutic concept break down into harmless lipids, amino acids and sugars. That means there are fewer adverse side effects.” 

Stupp’s research group has designed many peptide-based materials for different therapeutic purposes. To develop a peptide amphiphile that treats neurodegenerative diseases, his team added a natural sugar called trehalose. Normally, when placed in water, peptide amphiphiles self-assemble into stable nanofibers. But when the team added trehalose, the peptide amphiphiles instead formed destabilized 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 fibers. Less stable fibers, on the other hand, become more dynamic — and more likely to find and interact with toxic proteins. 

“Unstable assemblies of molecules want to interact with and bond to other molecules,” says Stupp. “If the nanofibers were stable, they would happily ignore everything around them.” 

Searching for stability, the nanofibers bond to amyloid-beta proteins, a key culprit implicated in Alzheimer’s disease. But the nanofibers don’t just stop the amyloid-beta proteins from clumping together. The nanofibers fully incorporate the proteins — permanently trapping them into stable filaments. 

“That means the nasty amyloid-beta proteins, which would have formed amyloid fibers, can no longer penetrate the neurons and kill them,” says Stupp. “It’s like a cleanup crew for misfolded proteins.” 

Laboratory tests using human neurons derived from stem cells showed the trehalose-coated nanofibers significantly improved the survival of neurons when exposed to the toxic amyloid-beta protein.