December 3, 2020

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

A faulty transport of amyloid-{beta} (A{beta}) across the blood-brain barrier (BBB), and its diminished clearance from the brain, contributes to neurodegenerative and vascular pathologies, including Alzheimer disease (AD) and cerebral amyloid angiopathy, respectively. At the BBB, A{beta} efflux transport is associated with the low-density lipoprotein receptor-related protein 1 (LRP1). However, the precise mechanisms governing the A{beta} 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 A{beta} clearance across the BBB. We further demonstrate whether risk factors for AD, A{beta} expression and ageing, impact on native syndapin-2 expression in the brain endothelium, with syndapin-2 mediating A{beta} transcytosis. Both increased A{beta} 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 A{beta} 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 A{beta}, and thus proposing a new measure to assess AD and ageing, as well as, a potential target for counteracting the build-up of brain A{beta}.

 bioRxiv Subject Collection: Neuroscience

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