Ibraheem, A. | bioRxiv Science

bioRxiv2025

Systemic administration of PD-L1 blocking antibodies leads to removal of senescent microglia

Senescent microglia develop during aging and Alzheimers disease (AD), driving chronic neuroinflammation. Here we hypothesized that the previously observed disease-modifying effects of PD-1/PD-L1 blockade occur through clearance of senescent microglia. Using CyTOF, we found that a single systemic anti-PD-L1 injection leads to rapid elimination of senescent microglia in 5xFAD and aged wild-type mice, independently of Fc effector function, while increasing homeostatic microglia. These findings suggest that immune rejuvenation via PD-L1 blockade promotes disease modification in AD through senescent-microglial elimination.

neuroscience↗

bioRxiv2025

Alzheimer's disease causes bone marrow myelopoiesis dysfunction

Accumulating evidence suggests that both innate and adaptive immunity play crucial roles in combating Alzheimers disease (AD). Specifically, enhancing the homing of monocyte-derived macrophages to the affected brain has been shown to reduce local inflammation, decrease proteinopathy, rescue neurons, and mitigate cognitive decline. However, the factors limiting their spontaneous recruitment remain unclear. Using multi-omics techniques, we identified impaired myelopoiesis and monocyte development in both mice and AD patients. While not the primary cause of the disease, this impairment is associated with disease progression. In the 5xFAD mouse model, monocyte differentiation was found to be disrupted due to a maladaptive bone marrow (BM) response, driven by type I interferon (IFN-I) signaling. A similar phenotype was found in circulating monocytes from AD patients compared to healthy controls. Blocking IFN-I with monoclonal antibodies or using chimeric AD mice with BM from mice lacking the IFN-I receptor (IFNAR1) alleviated myelopoiesis dysfunction, normalized monocyte phenotypes, and reduced cognitive impairment. These improvements in myeloid function were accompanied by an increased homing of monocyte-derived macrophages in the AD brain. Our results reveal an unexpected dysfunction in BM myelopoiesis in the context of neurodegeneration and support the emerging concept that neurodegenerative diseases are not solely brain-centric.

neuroscience↗