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Innovative Approach to Alzheimer’s Treatment Using Engineered Microglia
Researchers at the University of California, Irvine, have proposed a groundbreaking method of delivering therapeutic proteins throughout the brain, with the potential to enhance treatment for Alzheimer’s disease and other neurological disorders. By redesigning human immune cells known as microglia, the team has created dynamic cellular “couriers” that can address specific brain pathologies and release targeted treatments exactly where they are needed most.
The study, backed by the National Institutes of Health and published in Cell Stem Cell, marks the inaugural demonstration of induced pluripotent stem cell-derived microglia being genetically modified to recognize disease-specific changes in the brain, such as the presence of amyloid plaques characteristic of Alzheimer’s disease. These modified microglia can release enzymes that aid in breaking down these harmful proteins, ultimately leading to reduced inflammation, preservation of neurons and synapses, and a reversal of several neurodegeneration indicators in mouse models.
For individuals and families affected by Alzheimer’s, this research promises a hopeful future where microglial-based therapies may effectively combat the severe impacts of neurodegeneration.
“Administering biologic medications to the brain has historically faced obstacles due to the blood-brain barrier,” explained Mathew Blurton-Jones, a UC Irvine professor of neurobiology and behavior and co-corresponding author of the study. “Our development offers a programmable, living delivery system that resides within the brain itself, activating only when and where it is needed, thus overcoming traditional delivery challenges.”
Utilizing CRISPR gene editing technology, the team was able to modify human microglia to produce neprilysin, an enzyme that specifically targets and degrades beta-amyloid, in response to a promoter that activates only in the vicinity of amyloid plaques. This method ensures a highly tailored and pathology-responsive therapy. In experimental models of Alzheimer’s, these engineered microglia effectively diminished beta-amyloid accumulation, safeguarded neuronal integrity, reduced synaptic damage, and mitigated inflammation, leading to a decrease in biomarkers associated with neuronal injury.
“Our findings reveal that strategically placing microglia in specific brain regions can significantly lower amyloid levels and other neuropathological traits associated with Alzheimer’s throughout the brain,” remarked Jean Paul Chadarevian, the study’s first author and a postdoctoral scholar in Blurton-Jones’s lab. “Because the therapeutic proteins are produced only in response to the presence of amyloid plaques, our approach is both highly precise and broadly effective.”
The research also extended its exploration to responses from human microglia in models of brain cancer and multiple sclerosis. In these scenarios, the engineered microglia exhibited distinct gene expression patterns, indicating a promising capacity for customization according to various central nervous system conditions.
“This research paves the way for a novel class of brain therapies,” stated Robert Spitale, a UC Irvine professor of pharmaceutical sciences and co-corresponding author on the study. “Rather than relying on synthetic drugs or viral vectors, we are harnessing the brain’s own immune cells as precision delivery vehicles for therapeutic agents.”
While the findings are promising, the researchers emphasized that significant work is necessary to translate these discoveries into human clinical trials. This includes ensuring long-term safety and developing scalable production methods. However, because these microglia can be derived from induced pluripotent stem cells, there is the potential for utilizing a patient’s own cells, which could mitigate the risk of immune rejection.
Supporting contributions also came from Hayk Davtyan, Alina L. Chadarevian, Jonathan Hasselmann, and others, collaborating through UC Irvine’s Department of Neurobiology & Behavior, the Institute for Memory Impairments and Neurological Disorders, and the Sue & Bill Gross Stem Cell Research Center. Funding for the research was provided by the National Institute on Aging, the California Institute for Regenerative Medicine, and the Cure Alzheimer’s Fund.
Understanding Microglia
About Microglia
Microglia serve as vital immune cells within the central nervous system, playing a critical role in maintaining brain health. They function similarly to white blood cells elsewhere in the body, acting as the primary defense against infection and injury.
Think of microglia as the brain’s dedicated surveillance team. They are continually scanning for signs of harm—such as pathogens, damaged cells, or toxic proteins—and respond by engulfing and digesting these threats through a process known as phagocytosis. Furthermore, microglia are integral in regulating inflammation, and they support neuronal function and adaptability throughout brain development and aging.
In the context of diseases like Alzheimer’s, microglia are frequently located near amyloid plaques, where they become activated in an attempt to clear out these toxic entities. However, their activity can become maladaptive in chronic conditions, leading to neuroinflammation and exacerbating damage to neurons. Given their dual role in neuroprotection and potential neurotoxicity, microglia are a primary focus of current neurological research and therapeutic development.
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