Researchers repair faulty brain circuits with nanotechnology

Researchers repair faulty brain circuits with nanotechnology

Working with human and mouse tissues, Johns Hopkins Medicine researchers report new evidence that a protein extracted from certain "helper" cell populations of the brain, called astrocytes, plays a specific role in forming connections between neurons necessary for learning and forming new memories.

Using genetically engineered and reproduced mice with fewer such connections, the researchers conducted proof-of-concept experiments that showed that they could deliver corrective proteins via nanoparticles to replace the missing protein needed for "Road repair" on the defective neural route.

As these connectivity networks are lost or damaged by neurodegenerative diseases such as Alzheimer's disease or certain types of intellectual disabilities such as Norrie's disease, the researchers say their discoveries advance efforts to restore and repair networks and potentially restore normal brain function.

The results are described in the May issue of Nature Neuroscience.

"We are examining the fundamental biology of astrocyte function, but may have discovered a new target for someday intervention in neurodegenerative diseases with new treatments," said Jeffrey Rothstein, MD, Ph.D., director of the John W. Griffin Brain Science Institute and Professor of Neurology at the Johns Hopkins University School of Medicine.

"Although astrocytes all seem to resemble each other in the brain, we had the impression that they could play specialized roles in the brain because of regional differences in brain function and because of changes observed in certain diseases", said Rothstein. "The hope is that learning to exploit individual differences in these distinct populations of astrocytes could allow us to direct brain development or even reverse the effects of certain brain conditions, and our current studies have advanced this hope. "

In the brain, astrocytes are the supporting cells that serve as guides for directing new cells, promoting chemical signaling, and cleaning the byproducts of brain cell metabolism.

The Rothstein team has focused on a particular astrocyte protein, the glutamate-1 transporter, which, according to previous studies, would have been lost in the astrocytes of certain parts of the brain with neurodegenerative diseases. As a biological aspirator, the protein normally aspirates the chemical glutamate "messenger" spaces between neurons after sending a message to another cell, an essential step to stop the transmission and prevent the formation of toxic levels of glutamate.

When these glutamate transporters disappear from certain parts of the brain – such as the motor cortex and spinal cord in people with Amyotrophic Lateral Sclerosis (ALS) – glutamate trails far too long, sending messages that excite and destroy cells.

To determine how the brain decides which cells need glutamate transporters, Rothstein and his colleagues focused on the region of DNA in front of the gene that usually controls the on-off switch needed to manufacture of the protein. Genetically modified mice start to glow in all the cells where the gene is activated.

Normally, the glutamate transporter is activated in all astrocytes. But, using between 1,000 and 7,000 bits of DNA code from the glutamate on-off switch, all brain cells glowed, including neurons. This is only when the researchers tried the largest sequence of an 8,300-bit DNA code from this location as researchers began to see a selection in red blood cells. These red blood cells were all astrocytes, but only in some layers of the cerebral cortex in mice.

Because they could identify these "8.3 red astrocytes", the researchers thought that they could have a specific function different from that of other astrocytes in the brain. To find out more precisely what these 8.3 red astrocytes are doing in the brain, the researchers used a cell sorting machine to separate the red astrocytes from the non-stained cortical tissue from the mouse brain and then identified the genes that were activated much higher. normal levels in red compared to unstained cell populations. The researchers found that the red 8.3 astrocytes activate high levels of a gene that encodes a different protein called Norrin.

The Rothstein team took neurons from the normal mouse brain, treated them with Norrin, and discovered that these neurons were developing more "branches" – or extensions – used to transmit chemical messages into brain cells . Next, according to Rothstein, the researchers examined the brains of Norrin-deficient mice and found that these neurons had fewer branches than Norrin's healthy mice.

In another series of experiments, the research team took Norrin's DNA code plus the 8,300 "location" DNAs and badembled them into nanoparticles to deliver. When Norrin nanoparticles were injected into the brains of Norrin-developed mice, the neurons of these mice began to multiply rapidly, suggesting that neural networks could be repaired. They also repeated these experiments with human neurons.

Rothstein notes that Norrin protein mutations that reduce protein levels in humans cause Norrie's disease – a rare genetic condition that can lead to blindness in early childhood and intellectual disability. Since researchers have been able to develop new branches for communication, they think that it might one day be possible to use Norrin to treat certain types of intellectual disabilities such as Norrie's disease.

For their next steps, researchers are investigating whether Norrin can repair connections in the brain of animal models with neurodegenerative diseases. To prepare for a potential success, Miller and Rothstein filed a patent for Norrin.

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The other authors of the publication are: Sean Miller, Thomas Philips, Namho Kim, Raha Dastgheyb, Zhuoxun Chen, Yi-Chun Hsieh, Gavin Daigle J., Jeannie Chew, Svetlana Vidensky, Jacqueline Pham, Ethan Hughes, Michael Robinson, Rita Sattler , Jung Soo Suk, Dwight Bergles, Norman Haughey, Mikhail Pletnikov and Justin Hanes of Johns Hopkins, and Malika Datta and Raju Tomer of Columbia University.

This work was funded by grants from the Research Fellowship Program of the Graduate Foundation of the National Science Foundation and the National Institute of Neurological Disorders and Stroke (R01NS092067, R01NS094239).

This story was published on: 2019-07-30. To contact the author, please use the contact information in the article.

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