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Chadarevian et al. highlighted in Alzforum

Delivery Courier? Microglia Drop Neprilysin Off Near Plaques in Brain

The blood-brain barrier border protects the brain by regulating the flow of molecules, peptides, and cells, but it also keeps out many therapeutics. Now, researchers have harnessed the power of a resident drug courier, i.e., microglia.
  • Researchers genetically engineered human iPSC-microglia to deliver neprilysin when the cells are near amyloid plaques.
  • Both local injection and brain-wide engraftment of neprilysin-secreting microglia reduced Aβ pathology.
  • Only widespread engraftment helped reduce pathologies and improve neuronal density in the subiculum.

Mathew Blurton-Jones and his team at the University of California, Irvine, have engineered human iPSC-derived microglia (iMG) to ferry protein therapeutics into the brain. They CRISPR-engineered the immune cells to express the Aβ-degrading enzyme neprilysin, but only in areas where the cells encounter amyloid plaques. When the researchers injected the couriers into mouse models of Alzheimer’s disease, the cells not only reduced the amount of amyloid, but also improved downstream aspects of Alzheimer’s pathogenesis. “While there are, of course, other approaches to reduce [Aβ] levels, this study demonstrated the powerful potential of iPSC-microglia to provide a novel immune cell therapy for a broad array of neurological diseases,” senior author Blurton-Jones wrote to Alzforum.

Read the full article here.

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Blurton-Jones Lab Highlighted by UCI MIND

Engineered microglia show promise for treating Alzheimer’s and other brain diseases UC Irvine team develops cell-based platform for brain-wide delivery of therapeutic proteins

University of California, Irvine scientists have unveiled a groundbreaking new way to deliver disease-fighting proteins throughout the brain, potentially revolutionizing the treatment of Alzheimer’s disease and other neurological disorders. 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 recently in Cell Stem Cell, demonstrates for the first time that induced pluripotent stem cells (iPSC) – derived microglia can be genetically programmed to detect disease-specific brain changes – like amyloid plaques in Alzheimer’s disease – and to then specifically respond to pathology by releasing 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.

To read the full article, click here.

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Chadarevian et al. publish in Cell Stem Cell

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins

Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer’s disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.

Highlights
  • iPSC-microglia enable pathology-responsive delivery of therapeutic proteins
  • Both regional and CNS-wide microglial secretion of neprilysin reduces Aβ pathology
  • Neprilysin delivery also lowers inflammation, dystrophic neurites, and plasma NfL
  • iPSC-microglia can be harnessed to provide a promising new cell therapy platform
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Blurton-Jones lab presents at ADPD 2025 in Vienna, Austria

Dr. Mathew Blurton-Jones and Jean Paul Chadarevian were invited to share their research at this year’s ADPD 2025 (April 1-5) International Conference on Alzheimer’s and Parkinson’s Diseases.

Dr. Mathew Blurton-Jones was invited to moderate the session on cell replacement therapy & diagnostics, where he presented key findings highlighting the differences between CNS-wide engrafted human monocytes and iPSC-microglia.  Dr. Jean Paul Chadarevian was also selected to present his research harnessing human iPSC-microglia for CNS-wide delivery of therapeutic peptides.

Congratulations to all the attendees and participants of ADPD 2025!

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Blurton-Jones lab attends Emerging Scientists Symposium at UCI

The UCI MIND trainee-led organization ReMIND held its annual Emerging Scientists Symposium at the UCI Student Center. This yearly event gives UCI MIND graduate students, medical students, and post-doctoral scholars opportunities to get out of the laboratory to present their work through posters and oral presentations, to network with and learn from each other, and to generally stay excited about research and the progress we are making toward understanding and discovering solutions for Alzheimer’s disease and related disorders (ADRD) research. Congratulations to Zahara Keulen, Dr. Ghazaleh Eskandari-Sedighi, and Dr. Jean Paul Chadarevian on your selection and presentations!

Read more about this important event: https://mind.uci.edu/remind_train/