The role of syndapin-2 mediated transcytosis across the blood-brain barrier on amyloid-β accumulation in the brain

Abstract

AbstractA deficient transport of amyloid-(Aβ) across the blood-brain barrier (BBB), and its diminished clearance from the brain, contributes to neurodegenerative and vascular pathologies, including Alzheimer’s (AD) and cerebral angiopathy, respectively. At the BBB, Aβ efflux transport is associated with the low-density receptor-related protein 1 (LRP1). However, the precise mechanisms governing Aβ transport across the BBB, in health and disease, remain to be fully understood. Recent evidence indicates that the LRP1 transcytosis occurs through a tubulation-mediated mechanism stabilised by syndapin-2. Here, we show that syndapin-2 is associated with Aβ clearance via LRP1 across the BBB. We further demonstrate that risk factors for AD, Aβ expression and ageing, are associated with a decline in the native expression of syndapin-2 within brain endothelium. Our data reveal that the syndapin-2-mediated pathway, and its balance with the endosomal sorting, are important for Aβ clearance proposing a measure to evaluate AD and ageing, as well as a target for counteracting Aβ build-up. Moreover, we provide evidence for the impact of the avidity of Aβ assemblies in their trafficking across the brain endothelium and in LRP1 expression levels, which may affect the overall clearance of Aβ across the BBB.