On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias

XH Tian and DM Leite and E Scarpa and S Nyberg and G Fullstone and J Forth and DL Matias and A Apriceno and A Poma and A Duro-Castano and M Vuyyuru and L Harker-Kirschneck and A Saric and ZP Zhang and P Xiang and B Fang and YP Tian and L Luo and L Rizzello and G Battaglia, SCIENCE ADVANCES, 6, eabc4397 (2020).

DOI: 10.1126/sciadv.abc4397

The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor-related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super- resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high- avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across.

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