The latest class of Alzheimer’s disease drugs has shown for the first time that they can slow the progression of Alzheimer’s disease itself. These treatments usually allow patients to remain independent for about another 10 months. The drug, known as a monoclonal antibody, works by lowering levels of amyloid, a harmful protein that builds up in the brain. However, patients must receive large doses via infusion once or twice a month.
Scientists are currently looking for ways to make treatments less frequent and more effective. Researchers at Washington University School of Medicine in St. Louis have developed an experimental cellular immunotherapy that requires only one injection. In mice, the treatment prevented amyloid plaque formation when given before plaque accumulation began. When this treatment was given to mice that already had plaques, the amount of amyloid in their brains was reduced by about half.
The findings were published on March 5th. science.
Turn astrocytes into plaque-clearing cells
This new strategy is inspired by CAR-T cell therapy used in cancer treatment. In these treatments, immune T cells are genetically engineered to identify and attack cancer cells. In this approach to Alzheimer’s disease, scientists modified different types of cells. They equipped astrocytes, a common type of brain cell, with a CAR homing device that allows the cells to latch onto and destroy specific targets.
These engineered CAR astrocytes act like powerful cleaning cells in the brain. Its design allows it to find and remove harmful proteins that contribute to cognitive decline.
“This study represents the first successful attempt to manipulate astrocytes to specifically target and clear amyloid-beta plaques in the brains of Alzheimer’s disease mice,” said study lead author Marco Colonna, MD, and Robert Locke Beliveau, MD, professor of pathology at WashU Medicine. “Although further research is needed to optimize this approach and address potential side effects, these results open exciting new opportunities to develop CAR astrocytes as immunotherapy for neurodegenerative diseases and even brain tumors.”
How amyloid plaques damage the brain
Alzheimer’s disease begins when a sticky protein called amyloid beta builds up in the brain, forming plaques. These deposits trigger a series of harmful changes that ultimately lead to brain atrophy and decline in cognitive function.
Normally, immune cells in the brain known as microglia help remove cellular waste. However, during neurodegenerative diseases such as Alzheimer’s disease, these cells can become overabundant and lose their ability to eliminate harmful substances from the brain.
Reprogram brain cells to remove amyloid
To reduce the burden on microglia, first author Dr. Yun Chen, then a graduate student working in Colonna’s lab, along with Barbara Burton, Ph.D., and David M. Holzman, M.D., Reuben M. Morris III Professor Emeritus of Neurology at the University of Washington School of Medicine, focused on astrocytes. Astrocytes are the most abundant cells in the brain and typically help maintain a healthy environment for neurons.
Dr. Chen re-engineered astrocytes to become specialized amyloid-clearing cells. He introduced genes that produce chimeric antigen receptors (CARs) into astrocytes by injecting mice with a harmless virus. When expressed on the surface of astrocytes, CAR allows the cells to capture and engulf amyloid beta protein. With this added ability, astrocytes focused on clearing amyloid beta plaques in mice prone to developing them. Astrocytes normally help maintain order in the brain.
Testing treatment in mice prone to Alzheimer’s disease
By about six months of age, mice with genetic mutations associated with a higher risk of Alzheimer’s disease begin to develop amyloid beta plaques that fill their brains. Chen, now a postdoctoral fellow in Holtzman’s lab, tested the treatment in two groups of these mice. One group received the virus carrying the CAR gene before plaques appeared, and the second group received treatment after their brains were already filled with plaques. The researchers then waited three months to evaluate the results.
In young mice, genetically engineered CAR astrocytes stopped plaque formation. By nearly 6 months of age, when the brains of untreated mice are usually filled with amyloid plaques, the treated mice had no detectable amyloid plaques.
In older mice whose brains were already filled with plaques when treatment began, the treatment reduced amyloid plaque levels by about 50 percent compared to mice given the virus without the CAR gene.
Possibility of single injection therapy
The researchers, with support from WashU’s Technology Management Office, have applied for a patent on their CAR-astrocyte engineering method.
“Like antibody drug therapy, this new CAR astrocyte immunotherapy is more effective when administered early in the disease process,” said Holtzman, a co-author of the paper. “But where it’s different, and what could make a difference in clinical care, is in the single injection that was successful in reducing the amount of harmful brain proteins in mice.”
Future possibilities for Alzheimer’s disease and brain tumors
The research team plans to continue refining the CAR-astrocyte therapy. Future research will focus on improving how precisely cells target harmful proteins while ensuring that normal brain cell activity is not disrupted.
Researchers also believe the technique could be applied to other diseases. By modifying the CAR homing device to recognize markers found on brain tumors, astrocytes could be redirected from debris removal to direct destruction of tumor cells. This strategy could ultimately lead to new treatments for brain tumors and other diseases that affect the central nervous system.
