Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid‐β and with neuroinflammatory cytokines

Immunotherapies are a promising strategy for the treatment of neurological diseases such as Alzheimer's disease (AD), however, transport of antibodies to the brain is severely restricted by the blood–brain barrier (BBB). Furthermore, molecular transport at the BBB is altered in disease, which may affect the mechanism and quantity of therapeutic antibody transport. To better understand the transport of immunotherapies at the BBB in disease, an in vitro BBB model derived from human induced pluripotent stem cells (iPSCs) was used to investigate the endocytic uptake route of immunoglobulin G (IgG). In this model, uptake of fluorescently labeled IgGs is a saturable process. Inhibition of clathrin‐mediated endocytosis, caveolar endocytosis, and macropinocytosis demonstrated that macropinocytosis is a major transport route for IgGs at the BBB. IgG uptake and transport were increased after the addition of stimuli to mimic AD (Aβ1–40 and Aβ1–42) and neuroinflammation (tumor necrosis factor‐α and interleukin‐6). Lastly, caveolar endocytosis increased in the AD model, which may be responsible for the increase in IgG uptake in disease. This study presents an iPSC‐derived BBB model that responds to disease stimuli with physiologically relevant changes to molecular transport and can be used to understand fundamental questions about transport mechanisms of immunotherapies in health and neurodegenerative disease. Immunotherapies are a promising strategy for the treatment of neurological diseases such as Alzheimer's disease (AD), however, transport of antibodies to the brain is severely restricted by the blood‐brain barrier (BBB). This study presents an in vitro BBB model derived from human induced pluripotent stem cells that responds to disease stimuli (Aβ1–40, Aβ1–42, TNF‐α, IL‐6) with physiologically relevant changes to transport of IgG, that can be used to understand questions about transport mechanisms of immunotherapies in health and neurodegenerative diseases.