Sugar-coated nanotherapy trap toxic proteins in Alzheimer’s disease

Northwestern University scientists have developed an innovative nanotherapy that targets the root causes of Alzheimer’s disease and other neurodegenerative diseases directly.

The treatment is basically a “cleaner” of misfolded proteins in the brain, significantly improving neuron survival in lab tests. The method, published Wednesday in the Journal of the American Chemical Society, could slow the disease progression before it damages brain cells by trapping toxic proteins.

Targeting destructive proteins in their source

In diseases like Alzheimer’s and ALS, protein protein folding rates are misfolded and entangled around neurons, ultimately leading to cell death. This new approach intervenes in this new approach at an earlier stage of the disease process, rather than trying to treat symptoms.

“Our study highlights the exciting potential of molecularly designed nanomaterials to address the underlying causes of neurodegenerative diseases,” explained senior authors of the study. “In many of these diseases, proteins lose their functionally folded structure and aggregates allow destructive fibers to enter neurons and are highly toxic to them.”

The Northwest team found that their nanotherapy can effectively capture these harmful proteins before pooling them into toxic structures that can penetrate neurons. Once trapped, proteins will degrade harmlessly in the body.

Sweet solutions to complex problems

The researchers used peptide amphiphiles for treatment, a class of molecules found in famous drugs such as Ozempic. What makes this treatment unique is the addition of trehalose, a natural sugar found in plants, fungi and insects.

“Trehalose occurs naturally in plants, fungi and insects,” explains Zijun Gao, a Ph.D. Candidates for Stupp Labs and first authors of the paper. “It protects them from temperature changes, especially dehydration and freezing. Others have found that trehalose can protect many biological macromolecules, including proteins. So we wanted to see if we could use it to stabilize the wrong protein.”

How nanotherapy works

When added to water, the peptide amphiphiles self-assemble into trehalose-coated nanofibers. Surprisingly, the researchers found that trehalose actually disrupted the stability of these nanofibers, which turned out to be beneficial.

The resulting unstable nanofibers actively seek and bind to toxic amyloid proteins associated with Alzheimer’s disease. Once bound, the nanofibers permanently incorporate these proteins into their structure, thereby effectively neutralizing them.

“Then, it’s no longer an amphiphilic fiber of the peptide,” Stup said. “But a new mixed structure, including peptide amphiphilic and amyloid proteins. This means that nasty amyloid proteins will get trapped in amyloid, which are trapped in trapped amyloid.

Promising outcomes of nerve survival

Laboratory tests using human neurons from stem cells showed significant results. When neurons are exposed to toxic amyloid proteins:

• Untreated neuron death
• Neurons treated with celestial coated nanofibers show a significantly improved survival rate
• Motor and cortical neurons are protected
• The therapy effectively prevents the formation of the most toxic early amyloid structures

The microscopic images clearly show the difference – untreated neurons exposed to amyloid proteins mainly appear red (death), while treated neurons mainly are green (live).

New mechanism with security advantages

This approach is significantly different from most current Alzheimer’s treatments, which usually target fully formed amyloid plaques or attempt to reduce inflammation. By intervening during the disease process, this treatment may prevent damage before it occurs.

The therapy also has potential safety advantages. “The advantage of peptide-based drugs is that they degrade into nutrients,” Stup notes. “The molecules in this novel therapeutic concept break down into harmless lipids, amino acids and sugars. This means fewer adverse side effects.”

According to the World Health Organization, an estimated 50 million people worldwide suffer from neurodegenerative diseases, and the need for effective treatment is urgent. Although current therapies offer limited relief, this new approach may change the way these diseases are treated.

What does this mean for future patients? Stupp believes that this therapy may be most effective in early stages of the disease and may be used in combination with other therapies. “Our therapy may be most effective when targeting diseases at an earlier stage – before summarizing proteins into the cells,” he said. “But diagnosing these diseases early is challenging. So it can be combined with treatments targeting the symptoms of the later stages of the disease. Then, it can be dual.”