Dr. Hayk Davtyan gave a talk and poster ‘Human blood monocytes and iPSC-microglia exhibit differing proteomic, transcriptional and functional properties following engraftment with the adult mammalian brain‘ at the ISSCR 2024 conference in Hamburg Germany.
Joia Capocchi was awarded the James Tait Goodrich Award for excellence in Neurobiology at the 2024 CNLM Awards Ceremony. Joia was also awarded the Barry Goldwater Scholarship at the 2024 Provost luncheon. Congratulations on your outstanding achievements!
Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
Dr. Jean Paul Chadarevian and Joia K. Capocchi attend 2024 Keystone Symposia on Neurodegeneration in Santa Fe, NM where Jean Paul presented, “Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy“.
Dr. Blurton-Jones (Examining the therapeutic potentical of microglial transplantation in chimeric models of AD and FTD) and Dr. Davtyan (Human Monocytes remain transcrptionally and functionally distinct from microglia despite long-term brain engraftment) presented at the International Society of Molecular Neurodegeneration 2024 conference on aging, immunity, and peripheral factors in neurodegenerative disease in Seoul, Korea.
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!
