The adult human brain has limited capacity to repair or regenerate neurons lost to Alzheimer's disease, the most common type of dementia. Existing treatments can slow disease progression but do not reverse cognitive decline. In a study publishing in the Cell Press journal Cell Biomaterials on August 26, researchers show that engineered nanoparticles can not only regenerate neurons in human brain organoids but also restore neural circuits and improve cognition in mice.
"The new neurons can become mature and survive," says corresponding author Peisheng Xu, a professor of pharmaceutics at the University of South Carolina. "We also confirmed much higher neuron density in the brains of treated mice."
Xu's team studied a polymer nanogel system called Nano-ERASER that uses antibodies to degrade targeted proteins. They used the system to permeate the blood-brain barrier and enter astrocytes, which are star-shaped support cells abundant in the central nervous system. Within the astrocytes, Nano-ERASER deployed antibodies to break down a protein called PTBP1, triggering the astrocytes to convert to neurons.
Compared to gene-editing tools like CRISPR, Nano-ERASER does not modify DNA and its cell reprogramming is reversible.
"We hope this can be more effective and also safer," Xu says. "We don't need to worry about the potential side effects caused on the genetic level."
First, the researchers applied Nano-ERASER to human astrocyte cultures, as well as human organoids designed to mimic brains with Alzheimer's disease. In both models, PTBP1 levels were reduced, prompting the conversion of astrocytes to neurons. Further testing revealed these new neurons were functional.
Next, the team treated mice with Alzheimer's disease. Over several weeks, their nesting skills recovered, and they completed a water maze more efficiently than before, suggesting improved learning and memory. In addition, the mouse brains showed increased neuron density and reduced neuroinflammation and amyloid-beta protein buildup, a hallmark of Alzheimer's disease.
"After just two injections, these mice became smarter," Xu says. "Even after one injection, we already saw these mice's behavior differ from that of the nontreated ones."
The findings mark a critical step in regenerative neuroscience, Xu says, in part because previous research has debated whether PTBP1 suppression alone could induce in vivo neuroregeneration.
Though this study does not prove that Nano-ERASER treats Alzheimer's disease in humans, Xu says it offers a roadmap for a potential cure. He and his colleagues plan to evaluate the platform for longer-term efficacy, test it in nonhuman primates, and one day begin human clinical trials.
"If we can advance it to the clinic, then we can have hope for patients with Alzheimer's disease," Xu says.
