Speaker
Description
Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet current therapies have limited efficacy. Immune responses, primarily from microglia and regulatory adaptive immune cells, are closely linked to the pathological changes in amyloid-beta and tau observed in AD. We previously demonstrated that microglia in adult mice can be replaced through bone marrow transplantation (BMT), leading to improved cognitive and behavioral features in an AD model. However, the conditioning regimen was highly toxic, and single-cell analysis capabilities were limited at the time. Recent advances in reducing BMT toxicity have led us to explore a safer protocol, which has shown strong tolerability in older patients with and without cancer, potentially enabling cell-based modulation of the brain’s immune landscape in AD.
Methods: Wild-type recipient mice (C3B6F1) were conditioned with anti-thymocyte serum (ATS), low-dose total lymphoid irradiation (TLI), total body irradiation (TBI), and the CSF1R inhibitor PLX3397 before transplantation with whole bone marrow (BM) from sex- and age-matched Balb/c donors. CD45+ cells from the brain were sorted into donor and recipient populations based on haplotype and analyzed at the single-cell level.
Results: We observed sustained multilineage donor mixed chimerism in peripheral and hematopoietic tissues three months post-transplant, with similar chimerism levels detected in the brain. Single-cell RNA sequencing revealed a comprehensive immune map, capturing diverse microglial populations, including border-associated microglia (BAM) clusters, as well as T cells (CD4+ and CD8+), NK cells, and B cells. BM-derived microglia displayed distinct transcriptional profiles from resident microglia, and ongoing work aims to elucidate their phenotypic and functional differences.
Conclusions: Our results prompt further testing of this approach to modulate the immune environment in neurodegenerative mouse models and assess whether this therapy can delay or prevent neurodegeneration in AD.
| Author(s) | Amalia Perna*, Cameron S Bader, Kathleen S Montine ,Everett Mayer, Thomas J Montine |
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| Affiliation(s) | Department of Pathology Stanford University School of Medicine Stanford CA United States, Division of Blood and Marrow Transplantation Department of Medicine Stanford University School of Medicine Stanford CA United States, Department of Pathology Stanford University School of Medicine Stanford CA United States, Division of Blood and Marrow Transplantation Department of Medicine Stanford University School of Medicine Stanford CA United States, Department of Pathology Stanford University School of Medicine Stanford CA United States. |
