Neurons have been created from a different type of brain cell that usually supports them. Nerve cell death is a hallmark of Alzheimer鈥檚 disease, but a cage of nanoparticles containing antibodies converted astrocytes, another type of brain cell, into neurons in mice with a version of the condition. This boosted the mice鈥檚 cognitive skills. The researchers behind the approach hope to test it in people in the next few years.
鈥淲e can replace lost neurons and also reverse Alzheimer鈥檚 disease progression [in mice],鈥� says at the University of South Carolina.
In Alzheimer鈥檚 disease, which , the proteins beta-amyloid and tau misfold and form clumps, known as plaques and tangles. This leads to neuroinflammation and, ultimately, nerve cell death.
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Researchers are increasingly exploring whether stimulating the growth of new neurons could treat Alzheimer鈥檚 disease and other neurodegenerative conditions. For instance, in 2020, scientists discovered that astrocytes 鈥� star-shaped cells that help neurons function 鈥� in the brains of mice with a version of Parkinson鈥檚 disease, which improved their motor skills.
This involved using CRISPR to genetically engineer the mice to deplete levels of a protein called PTBP1. This usually acts like a master switch that stops astrocytes from turning into neurons.
But such genetic approaches can alter regions of the genome you didn鈥檛 intend to target. 鈥淵ou can sometimes cut the wrong places, causing permanent genetic changes that may be harmful,鈥� says Xu.
To address this issue, he and his colleagues have developed another way to deplete PTBP1. They designed a drug called TN-PTBP1 that packages PTBP1-targeting antibodies within a cage of nanoparticles that shuttles them across the blood-brain barrier.
The drug enters cells in the brain, including astrocytes, where the antibodies bind to and substantially deplete PTBP1. After about a week, the antibodies are recycled by the cell, says Xu.
The team has now tested this in brain organoids made up of clumps of astrocytes and neurons, which were grown from human stem cells in a lab dish. This showed that TN-PTBP1 converts astrocytes into neurons.
Next, the researchers tried the approach in 12 mice that had been genetically engineered to develop a condition mimicking Alzheimer鈥檚. Prior to receiving TN-PTBP1, brain imaging revealed that these mice had lost a substantial number of neurons, similar to what is seen in moderate-to-severe Alzheimer鈥檚 disease, says Xu. The mice struggled to build nests and performed poorly in a memory test that involved navigating a maze.
The team intravenously injected half of the mice with TN-PTBP1 twice over two weeks, while the rest received saline injections. Two weeks later, the mice that received TN-PTBP1 were able to nest and navigate the maze at a similar level to another group of mice without the version of Alzheimer鈥檚, while the saline group showed no change. 鈥淭here鈥檚 clearly an improvement, which is very thought-provoking,鈥� says at the University of Cambridge.
When the researchers analysed samples of the mice鈥檚 hippocampi, an area of the brain involved in memory and learning, they found that TN-PTBP1 had caused new neurons to sprout in the brain. 聽
They are now planning more studies in mice where astrocytes are labelled with fluorescent tags to track whether TN-PTBP1 is really behind those cells converting into neurons, says Xu. The researchers also hope to test the approach in monkeys and people in the next few years, he says.
The mice showed no signs of side effects, but future work should explore whether the newly formed neurons safely integrate into the brain鈥檚 networks without disrupting their function over the long term, says at King鈥檚 College London. 鈥淲e need to check [whether] these neurons [would] be beneficial, rather than screwing up the network.鈥�
But with proper testing, the potential of this drug could be huge, he says. It 鈥渃ould have an enormous effect on the treatment of many brain diseases鈥�, including schizophrenia, motor neuron disease (such as ALS) and Parkinson鈥檚 disease, he says.
Cell Biomaterials
