Increased tau expression in theAPOE4blood-brain barrier model is associated with reduced anti-tau therapeutic antibody deliveryin vitro

Abstract

AbstractTau protein is a critical driver of neurodegeneration and an important drug target in Alzheimer’s disease (AD). Tau-specific immunotherapy has emerged as a promising treatment strategy for AD, however the therapeutic efficacy of anti-tau antibodies may be limited by their insufficient delivery across the blood-brain barrier (BBB). The apolipoprotein E4 allele (APOE4) is the strongest genetic risk factor for sporadic AD and is known to influence tau-mediated neurodegeneration. Interestingly, both tau andAPOE4have been implicated in the cerebrovascular pathology observed in AD. Yet, the crosstalk betweenAPOE4and tau at the level of the BBB and its consequences for anti-tau immunotherapeutics delivery, remain poorly understood. Here, we utilisedAPOE3- andAPOE4-carrying human iPSC-derived induced brain endothelial-like cells (iBECs) as a sporadic AD BBB model, determined the levels of endogenous tau in iBECs, and explored the transport of two novel monoclonal anti-tau antibodies, RNF5 and RN2N, across thein vitrobarrier. Our results demonstrate thatMAPTgene transcription, tau protein levels and tau phosphorylation are increased in iBECs in anAPOE4-related manner and are associated with reduced iBEC monolayer integrity and increased permeability to biologically inert fluorescent tracers. Additionally, elevated levels of intracellular tau inAPOE4cells were accompanied by the reduced passive permeability of therapeutic anti-tau antibodies through theAPOE4iBEC monolayer, which could be improved by the application of focused ultrasound and microbubble drug-delivery technology. Together, our study illustrates a new role forAPOE4and tau in human iBECs with potential implications for BBB dysfunction and anti-tau therapeutic antibody delivery.