Characterisation of a patient-derived iPSC-based model for studying the blood-brain barrier in Alzheimer's disease

The blood-brain barrier (BBB) comprised of the brain capillary endothelial cells (BCECs), with its tight junctions (TJ), transporters and receptors, regulates the passage of solutes, such as nutrients, metabolites, and xenobiotics, including drugs. In Alzheimer's disease (AD), characterised by the accumulation of amyloid-β peptide (Aβ) and the formation of hyperphosphorylated tau aggregates, a compromised BBB integrity was reported. There is a lack of knowledge about the effects of tau pathology on BBB function in AD. Advances in developing BBB models using human induced pluripotent stem cell (hiPSC)-derived BCECs have opened a new avenue for investigating AD-related changes in BBB functional integrity. Here, we characterised the BBB model derived from hiPSCs generated from an AD patient with a tau-related mutation (STBCi 062-A) versus the one based on a healthy person's cells (UKKi 011-A) in terms of mimicking AD-related changes in paracellular permeability, TJs, transporters, receptors and other proteins playing a role in BBB integrity. The STBCi 062-A-derived BCECs showed lower TEER values and increased permeability associated with downregulation of proteins regulating TJ organization and BBB integrity, as compared to UKKi 011-A-derived BCECs. We revealed AD-relevant increase in protein expression of efflux transporter BCRP and amino acid transporter ASCT1, as well as transferrin receptor protein 1 in the STBCi 062-A-derived BCECs compared to UKKi 011-A-derived BCECs. The developed AD-patient-hiPSC-derived BCEC model possesses several important characteristics that recapitulate changes in BBB integrity in AD and can serve as a robust tool for developing AD treatments.