Congratulations Lauren Le and Jasmine Nguyen on their First Place poster award at the UCI Undergraduate Research Symposium 2024 presenting the interdisciplinary UROP project, “Engineering iPSC-derived Microglia for CNS-Wide Delivery of Disease Modifying Proteins in Alzheimer’s Disease Mice.”
Well done to all MBJ lab participants.
Examining the Diverse Pathological Consequences of Microglial Absence
Our understanding of microglia, the principal immune cells of the central nervous system (CNS), continues to evolve as new models and approaches shift our perception of these intriguing cells. Previously envisioned as passive guardians of the brain, microglia have since been shown to play critical roles in development, neuroplasticity, and neurological disease.To further understand the role of microglia in AD and the impact of microglial absence on the aging brain, my thesis studies utilized ‘FIRE mice’, a genetic model that lacks microglia. FIRE mice harbor a homozygous deletion within the Fms intronic regulatory element (FIRE) super-enhancer, leading to a loss of CSF1R expression and congenital absence of microglia. To examine the role of microglia in AD pathogenesis, I crossed FIRE mice with 5xfAD mice that develop robust beta-amyloid plaque pathology. Remarkably, I found that absence of microglia promotes the development of cerebral amyloid angiopathy (CAA), brain calcification, and cerebral hemorrhages in AD mice. Importantly, transplantation of wildtype microglia prevents each of these pathological changes. To determine whether microglia absence alone can also induce pathological changes within the aging brain, I further examined 9-10 month-old FIRE mice in comparison to wildtype littermates and explored the impact of postnatal microglial transplantation, demonstrating that prolonged absence of microglia leads to the development of astrogliosis, calcification, and seizures, mimicking many of the pathological features of a rare human primary microgliopathy. Taken together, my thesis studies have revealed important roles for microglia in protecting the brain against age- and disease-related development of vascular, and white matter pathologies. These findings not only deepen our understanding of microglia’s roles in neurodegenerative diseases, but also provide initial evidence to support microglial transplantation as a viable therapeutic approach for a variety of neurodegenerative diseases.
Congratulations Jean Paul on receiving the 2024 Carl W. Cotman Young Scholar Award at this years REMIND Emerging Scientists Symposium.
The Blurton-Jones Lab attends ADPD 2024 in Lisbon, Portugal with three talks and two presentations. Congratulations to our speakers and graduate student, Alina Lahian, on her poster presentation!
Engineering human induced pluripotent stem cells to enable microglial replacement therapy in the central nervous system
Immune cell therapies (ICT) are becoming more mature options for a variety of diseases. As the resident immune cell of the brain, microglia stand out as the ideal candidate for ICT approaches in the central nervous system. Combining recent advances in gene editing and iPSC-microglia (iMG) differentiation, we sought to investigate whether microglia could be harnessed to provide widespread delivery of therapeutic cells and proteins to the brain. Collectively our studies have revealed three principal findings: 1) iPSC-microglia can be widely engrafted into a recipient adult brain via an inhibitor-resistant protocol; 2) transplantation of CRISPR-corrected iPSC-microglia can prevent and even reverse neuropathologies in a mouse model of ALSP, a rare neurodegenerative disease caused by loss of microglia; and 3) iPSC-microglia can be genetically-engineered ex vivo to effectively deliver therapeutic proteins locally or CNS-wide in response to neuropathologies such as amyloid plaques. Together these findings suggest that patient-derived microglia could offer a promising new platform for the development of future immune cell therapies in the CNS.
