A new generation of Alzheimer’s disease drugs, the first to be shown to alter the course of Alzheimer’s disease, typically extends patients’ lives by 10 months. These antibodies, called monoclonal antibodies, reduce the buildup of amyloid, a harmful protein, in the brain and require high-dose infusions of the drug once or twice a month.
Now, to reduce the frequency of treatments and potentially increase the effectiveness of anti-amyloid therapy, researchers at Washington University School of Medicine in St. Louis have developed a new cellular immunotherapy that requires just one injection to prevent amyloid plaques from forming in mice before they start forming. Additionally, one treatment in mice that already had plaques reduced the amount of amyloid plaques by half.
The study was published March 5 in the journal Science.
Similar to CAR T-cell therapy used in cancer treatment (in which the immune system’s T cells are genetically engineered to attack cancer cells), this new approach equips cells, in this case brain cells called astrocytes, with CAR-homing devices to grab targets for destruction. These new CAR astrocyte cells have the ability to turn into supercleaners that remove damaged proteins from the brain that are involved in cognitive decline.
This study represents the first successful attempt to engineer astrocytes to specifically target and remove amyloid beta plaques in the brains of Alzheimer’s disease mice. Although further studies are 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. ”
Marco Colonna, MD, lead author of the study, and Robert Locke Beliveau, MD, professor of pathology at WashU Medicine.
remove brain waste
Alzheimer’s disease begins when a sticky protein called amyloid beta builds up in the brain, forming plaques, triggering a cascade of events that causes brain atrophy and cognitive decline. Microglia, immune cells found in the brain, are responsible for removing waste from the brain, but they can malfunction if overwhelmed in the context of neurodegenerative diseases.
To ease the cleaning burden on microglia, first author Yun Chen, Ph.D., then a graduate student in the lab of Colonna and David M. Holzman, MD, Barbara Burton, Ph.D., and Ruben M. Morris III Distinguished Professor of Neurology at WashU Medicine, turned astrocytes, the most abundant cell type in the brain, into amyloid cleaning machines. He custom designed a gene encoding a chimeric antigen receptor (CAR) and delivered it to astrocytes via a harmless virus injected into mice. The CAR, now present on the surface of astrocytes, enabled the cells to capture and engulf amyloid beta protein. Astrocytes (generally responsible for keeping the brain in order) used their newly acquired abilities to focus solely on clearing amyloid-beta plaques in mice, where they tend to accumulate.
By six months of age, mice with genetic mutations that increase the risk of developing Alzheimer’s disease in humans develop amyloid-beta plaques that saturate their brains. Chen, now a postdoctoral researcher in Holtzman’s lab, injected two groups of mice with a virus carrying the CAR-expressing gene. One was a young mouse before plaques formed, and the other was an older mouse with a brain saturated with plaque. Then he waited three months.
As young mice aged, CAR astrocytes prevented the development of amyloid beta plaques. At about six months of age, when the brains of untreated mice are normally saturated with harmful plaques, the brains of the treated mice were free of plaques. Meanwhile, older mice with saturated brain plaques at the time of treatment had a 50% reduction in the amount of amyloid beta plaques compared to mice injected with a virus lacking the CAR gene.
The researchers, in cooperation with WashU’s Technology Management Office, have filed a patent related to the approach used to manipulate CAR astrocytes.
“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.”
In future studies, the authors aim to continue improving CAR astrocyte immunotherapy by fine-tuning the design to better target harmful proteins while avoiding negative effects on normal brain cell function. Furthermore, by tailoring the CAR homing device to recognize specific markers on brain tumors, it may be possible to switch the function of astrocytes from clearing debris to directly killing tumor cells. Such approaches could provide promising new ways to treat brain tumors and other central nervous system diseases.
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Reference magazines:
Chen, Y. others. (2026). Targeting amyloid-β lesions with chimeric antigen receptor astrocyte (CAR-A) therapy. Science. DOI: 10.1126/science.ads3972. https://www.science.org/doi/10.1126/science.ads3972
