Posted on 23 June 2025
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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.
The problem:
A major hurdle in the treatment of neurodegenerative disease is delivering therapies effectively to the brain. The brain is a ‘privileged’ organ protected by the blood-brain barrier (BBB), a selectively permeable barrier that prevents many potentially harmful substances from passing from the blood into the central nervous system. This also prevents many drugs from reaching the brain via the blood and means they may have to be injected into the brain repeatedly, which is invasive, limits how much of the brain can be reached and can cause unwanted side effects.
What if we could engineer our own cells to do the work for us? Microglia are the brain’s resident immune cells. They can move around within the brain and respond to damage including the presence of amyloid beta plaques, the misfolded protein structures thought to be a driver of Alzheimer’s disease. There is evidence that age-related changes in the microglia are major contributors to neurodegenerative disease and brain ageing in general. In this study, researchers investigate whether microglia can be engineered to enhance amyloid beta clearance, potentially paving the way for them to be used as an Alzheimer’s therapy. While microglia would still need to be injected into the brain, they would adapt to their environment to specifically seek out diseased regions. They are also unable to form tumours – a potential problem with neural stem cell injection, which is another approach being explored for regenerating damaged brain regions.
The discovery:
The researchers first took human fibroblast cells and reprogrammed them into induced pluripotent stem cells (iPSCs). These iPSCs were then used to generate iPSC-derived microglia (iMGs). The researchers then used CRISPR gene editing, a precise gene-editing technology, to modify iMG to produce secreted neprilysin (sNEP). NEP is an enzyme not normally secreted by microglia that breaks down amyloid-beta, but the researchers placed the gene responsible for sNEP under the control of a special promoter called CD9. This is a genetic switch that activates sNEP production only in the presence of amyloid plaques, meaning that engineered microglia should only produce sNEP when they encounter amyloid.
Researchers then used a special mouse model engineered to lack its own microglia and to develop amyloid plaques. They transplanted the engineered iMG into the brains of these mice. The iMG successfully engrafted (integrated into the brain tissue) and produced NEP specifically in areas with amyloid plaques, which was associated with a significant reduction in plaques, fewer damaged nerve fibres and significantly less inflammation when compared to control mice injected with saline or with unmodified microglia. Importantly, they also saw a decrease in plasma neurofilament light chain (NfL), a biomarker indicating nerve damage.
The study also investigated how iMGs responded to two other brain pathologies: metastasised breast cancer and multiple sclerosis. They found that iMGs did respond differently to these conditions, and also identified some genetic promoters responsible for regulating this response and that could be used to deliver therapeutic molecules in these diseases.
The implications:
This is early research and should be considered a proof of principal at this stage, but it’s an enticing one. Scientists are increasingly using genetic techniques to develop smart ways of getting around the traditional limitations of drug delivery, in this case by using the body’s own immune cells as a targeted drug delivery system. However, animal models are notoriously bad models of neurodegenerative disease, because the techniques used to make the animals develop these conditions mean that they often bear limited resemblance to what happens in human brains over the course of an entire lifetime, even if the end result looks similar. Much more work will need to be done for this to ever reach the clinic, but we have one more tool in the toolkit.
Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins https://doi.org/10.1016/j.stem.2025.03.009
Title image by Bhautik Patel, Upslash
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