Engineered brain cells offer new hope for treating Alzheimer's

A new way to deliver disease-fighting proteins throughout the brain may improve the treatment of Alzheimer's disease and other neurological disorders, according to University of California, Irvine scientists. By engineering human immune cells called microglia, the researchers have created living cellular "couriers" capable of responding to brain pathology and releasing therapeutic agents exactly where needed.

The National Institutes of Health-supported study, published in Cell Stem Cell, demonstrates for the first time that microglia derived from induced pluripotent stem cells can be genetically programmed to detect disease-specific brain changes – like amyloid plaques in Alzheimer's disease – and then release enzymes that help break down those toxic proteins. As a result, the cells were able to reduce inflammation, preserve neurons and synaptic connections, and reverse multiple other hallmarks of neurodegeneration in mice.

For patients and families grappling with Alzheimer's and related diseases, the findings offer a hopeful glimpse at a future in which microglial-based cell therapies could precisely and safely counteract the ravages of neurodegeneration.

Delivering biologics to the brain has long been a major challenge because of the blood-brain barrier. We've developed a programmable, living delivery system that gets around that problem by residing in the brain itself and responding only when and where it's needed."

Mathew Blurton-Jones, UC Irvine professor of neurobiology and behavior and co-corresponding author on the study

Using CRISPR gene editing, the team modified human microglia to secrete neprilysin – an enzyme known to degrade beta-amyloid – under the control of a promoter that only activates near plaques. The result was a highly targeted and pathology-responsive therapy. In Alzheimer's mouse models, these engineered microglia reduced the buildup of beta-amyloid and protected against damage to neurons and synapses, curbed inflammation, and even lowered a biomarker of neuronal injury in the blood.

"Remarkably, we found that placing the microglia in specific brain areas could reduce toxic amyloid levels and other AD-associated neuropathologies throughout the brain," said Jean Paul Chadarevian, a postdoctoral scholar in the Blurton-Jones lab and first author on the study. "And because the therapeutic protein was only produced in response to amyloid plaques, this approach was highly targeted yet broadly effective."

In addition to Alzheimer's, the research explored how human microglia respond in models of brain cancer and multiple sclerosis. In both cases, the engineered cells adopted unique gene expression profiles – highlighting the potential to tailor them to a variety of central nervous system diseases.

"This work opens the door to a completely new class of brain therapies," said Robert Spitale, UC Irvine professor of pharmaceutical sciences and co-corresponding author on the study. "Instead of using synthetic drugs or viral vectors, we're enlisting the brain's immune cells as precision delivery vehicles."

The researchers noted that much work remains to translate this platform into human trials, including demonstrating long-term safety and developing methods for scalable manufacturing. However, because the microglia are derived from induced pluripotent stem cells, they could possibly be produced from a patient's own cells, reducing the risk of immune rejection.

Hayk Davtyan, Alina L. Chadarevian and Jonathan Hasselmann of UC Irvine, among others, also contributed to the study, which was a collaboration among the university's Department of Neurobiology & Behavior, Institute for Memory Impairments and Neurological Disorders, and Sue & Bill Gross Stem Cell Research Center.

Grants from the National Institute on Aging, the California Institute for Regenerative Medicine and Cure Alzheimer's Fund supported the research.