Syndapin-2 Mediates Amyloid-β Transcytosis at the Brain Endothelium: Implications in Alzheimer’s Disease

A faulty transport of amyloid-β (Aβ) across the blood-brain barrier (BBB), and its diminished clearance from the brain, contributes to neurodegenerative and vascular pathologies, including Alzheimer’s disease (AD) and cerebral amyloid angiopathy, respectively. At the BBB, Aβ efflux transport is associated with the low-density lipoprotein receptor-related protein 1 (LRP1). However, the precise mechanisms governing the Aβ transport across the BBB, in health and disease, remain to be fully understood. New evidences suggest that LRP1 transcytosis occur through a tubular mechanism mediated by an F-BAR protein, syndapin-2. We show here that syndapin-2 is associated with Aβ clearance across the BBB. We further demonstrate whether risk factors for AD, Aβ expression and ageing, impact on native syndapin-2 expression in the brain endothelium, with syndapin-2 mediating Aβ transcytosis. Both increased Aβ expression and ageing significantly decreased expression of syndapin-2. These are mirrored by an alteration of the endosome-associated protein Rab5, with an increase of expression with Aβ accumulation and ageing. Collectively, our data reveal that the syndapin-2-mediated pathway and its balance with endosomal sorting at endothelial level are critical for the clearance of neuronally-derived Aβ, and thus proposing a new measure to assess AD and ageing, as well as, a potential target for counteracting the build-up of brain Aβ.