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bioRxiv · 10.1101/2020.07.12.199869

Syndapin-2 mediates amyloid-β transcytosis at the brain endothelium: implications in Alzheimer's disease

Leite, D. M.·Seifi, M.·Swinny, J. D.·Battaglia, G.
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Abstract

A deficient transport of amyloid-(A{beta}) across the blood-brain barrier (BBB), and its diminished clearance from the brain, contributes to neurodegenerative and vascular pathologies, including Alzheimers (AD) and cerebral angiopathy, respectively. At the BBB, A{beta} efflux transport is associated with the low-density receptor-related protein 1 (LRP1). However, the precise mechanisms governing A{beta} 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 A{beta} clearance via LRP1 across the BBB. We further demonstrate that risk factors for AD, A{beta} 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 A{beta} clearance proposing a measure to evaluate AD and ageing, as well as a target for counteracting A{beta} build-up. Moreover, we provide evidence for the impact of the avidity of A{beta} assemblies in their trafficking across the brain endothelium and in LRP1 expression levels, which may affect the overall clearance of A{beta} across the BBB.

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Leite, D. M., Seifi, M., Swinny, J. D., Battaglia, G.. 2020-07-13. Syndapin-2 mediates amyloid-β transcytosis at the brain endothelium: implications in Alzheimer's disease. https://doi.org/10.1101/2020.07.12.199869

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