Syndapin-2 mediated transcytosis of amyloid-β across the blood–brain barrier

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