Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development but maintained across adult aging

Abstract Transferrin receptor (TfR)-mediated transcytosis across the blood-brain barrier (BBB) is a promising strategy to improve delivery of biologics to the central nervous system (CNS). However, it remains unclear whether age and aging-related diseases impact TfR expression and/or BBB transport capacity. Here, we used the TfR-targeted antibody transport vehicle (ATV TfR ) to enhance CNS delivery in healthy mice and in the 5xFAD mouse model of Alzheimer’s disease (AD). Healthy neonates exhibited the highest vascular TfR expression and ATV TfR brain exposure, whereas BBB transport capacity remained stable across adulthood. Additionally, neither TfR expression nor ATV TfR brain uptake changed significantly in 5xFAD mice. Further, vascular TfR expression in AD patient brains was similar to age-matched controls, suggesting that TfR transport may be conserved for AD in humans. The elevated TfR-mediated brain delivery observed in early mouse development suggests the potential of added efficacy in utilizing TfR platforms for the treatment of early childhood diseases. Preservation of ATV TfR transport in adult mice across healthy aging and in an AD model supports continued application of TfR platforms in age-related diseases.