Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development and maintained across aging and in an Alzheimer’s mouse model
Transferrin receptor (TfR)-targeting of biologics has emerged as a promising strategy to improve drug delivery across the blood-brain barrier (BBB). However, most preclinical studies evaluating TfR-enabled drugs have been conducted in young adult animals. It remains unclear whether age and aging-related diseases impact TfR protein levels and/or BBB transport capacity. Here, we utilized a previously described TfR-targeting antibody transport vehicle (ATV<sup>TfR</sup>) to investigate how healthy aging and disease progression in the 5xFAD mouse model of Alzheimer's disease (AD) impact TfR protein and TfR-mediated brain delivery. ATV<sup>TfR</sup> transport capacity remained stable across 3- to 24-month-old healthy mice and 5xFAD progression did not impair ATV<sup>TfR</sup> brain transport up to 10.5 months, despite significant amyloid burden. Interestingly, neonates exhibited significantly elevated levels of vascular TfR protein and ATV<sup>TfR</sup> brain exposure compared to adult mice. Furthermore, vascular TfR in AD patient brains was similar to age-matched controls, suggesting conserved TfR transport is also likely in human AD. Overall, our data demonstrates broad functional utility for TfR-based brain delivery in both healthy aging and in an AD mouse model. Additionally, elevated TfR-mediated brain delivery during early mouse development highlights the potential of added efficacy in utilizing such platforms in disease treatment of infants and children.
Authors
- Elysia Roche
- Isabel Becerra
- David Huynh (ORCID: https://orcid.org/0000-0003-1491-5829)
- David Joy (ORCID: https://orcid.org/0000-0001-9941-9538)
- Claire B. Discenza
- Y. Joy Yu Zuchero (ORCID: https://orcid.org/0000-0001-5183-7968)
- Nathalie Khoury
- Timothy Earr (ORCID: https://orcid.org/0000-0002-6686-0631)
- Kendra J. Lechtenberg (ORCID: https://orcid.org/0000-0002-3344-1289)
- Jason C. Dugas (ORCID: https://orcid.org/0000-0003-0849-9830)
- Roni Chau (ORCID: https://orcid.org/0000-0003-4861-563X)
- Johann Chow (ORCID: https://orcid.org/0009-0001-8170-6392)
- Hilda Solanoy (ORCID: https://orcid.org/0000-0002-3188-9928)
- Matthew Simon (ORCID: https://orcid.org/0000-0002-0065-6486)
- Amy Wing-Sze Leung
- Lily Sarrafha (ORCID: https://orcid.org/0000-0002-6168-2119)
- Kylie S. Chew (ORCID: https://orcid.org/0000-0003-4752-009X)
- Kirk R. Henne (ORCID: https://orcid.org/0000-0003-0370-2094)
- Michelle E. Pizzo (ORCID: https://orcid.org/0000-0003-4219-5996)
- Joseph W. Lewcock (ORCID: https://orcid.org/0000-0003-3012-7881)
- Hoang N. Nguyen (ORCID: https://orcid.org/0000-0001-6608-7581)
- Emmanuel S. Ojo
- Ryan J. Watts (ORCID: https://orcid.org/0000-0002-4973-5089)
- Vanessa O. Torres (ORCID: https://orcid.org/0000-0001-7302-7560)
- Meredith Calvert (ORCID: https://orcid.org/0000-0003-2893-959X)
- Darren Chan (ORCID: https://orcid.org/0000-0002-7913-9325)
- Raymond K. Tong (ORCID: https://orcid.org/0000-0002-7915-1850)
- Mabel Tong
- Robert G. Thorne
- Eric Liang
- Laura Furaso
Institutions
- University of Minnesota (US)
- Denali Therapeutics (United States) (US)
Publication Details
- Journal
- Journal of Cerebral Blood Flow & Metabolism
- Published
- 2025-08-16
- DOI
- https://doi.org/10.1177/0271678x251361997
- Citations
- 1
- Primary Topic
- Barrier Structure and Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.84