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

Abstract

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.

The Role of BAR Proteins and the Glycocalyx in Brain Endothelium Transcytosis

“…Interestingly, our recent study demonstrated that PACSIN-2 participates in the formation of tubular carriers for a fast transcytosis of LRP1 across BECs [7]. Furthermore, we also demonstrated that BECs employ PACSIN-2 for the clearance of amyloid-ß via LRP1 across the BBB [84]. Hence, our findings corroborate the hypothesis that PACSIN-2 facilitates a tubulation-mediated mechanism for transcytosis across BECs.…”

“…Surprisingly, even though BAR proteins and the GC are intrinsically associated with cell membranes and known to control the shape of the membrane, their role is often neglected in the brain endothelium. Numerous BAR proteins are enriched in a mammalian brain, and particular BAR proteins have been reported to be altered in CNS disorders, such as Alzheimer’s [ 29 , 84 ] and Huntington’s [ 127 , 128 ] disease, and epileptic seizures [ 129 ]. Thus, it appears that BAR proteins may have an important role in the brain that is worth further exploring.…”

Imaging Aβ aggregation by liquid-phase transmission electron microscopy

“…Aβ40 peptide (Bachem 4014442.1) was prepared into oligomer and fibril samples using previously described methods (44, 45, 57). The samples were characterized first using conventional solid-state TEM to confirm that the oligomers and fibril structures had formed as expected.…”