The Extent of Human Apolipoprotein A-I Lipidation Strongly Affects the β-Amyloid Efflux Across the Blood-Brain Barrier in vitro
Articolo
Data di Pubblicazione:
2019
Citazione:
The Extent of Human Apolipoprotein A-I Lipidation Strongly Affects the β-Amyloid Efflux Across the Blood-Brain Barrier in vitro / R. Dal Magro, S. Simonelli, A. Cox, B. Formicola, R. Corti, V. Cassina, L. Nardo, F. Mantegazza, D. Salerno, G. Grasso, M.A. Deriu, A. Danani, L. Calabresi, F. Re. - In: FRONTIERS IN NEUROSCIENCE. - ISSN 1662-4548. - 13(2019 May 16). [10.3389/fnins.2019.00419]
Abstract:
Much evidence suggests a protective role of high-density lipoprotein (HDL) and its major apolipoprotein apoA-I, in Alzheimer's disease (AD). The biogenesis of nascent HDL derived from a first lipidation of apoA-I, which is synthesized by the liver and intestine but not in the brain, in a process mediated by ABCA1. The maturation of nascent HDL in mature spherical HDL is due to a subsequent lipidation step, LCAT-mediated cholesterol esterification, and the change of apoA-I conformation. Therefore, different subclasses of apoA-I-HDL simultaneously exist in the blood circulation. Here, we investigated if and how the lipidation state affects the ability of apoA-I-HDL to target and modulate the cerebral beta-amyloid (A beta) content from the periphery, that is thus far unclear. In particular, different subclasses of HDL, each with different apoA-I lipidation state, were purified from human plasma and their ability to cross the blood-brain barrier (BBB), to interact with A beta aggregates, and to affect efflux across the BBB was assessed in vitro using a transwell system. The results showed that discoidal HDL displayed a superior capability to promote A beta efflux in vitro (9 x 10(-5) cm/min), when compared to apoA-I in other lipidation states. In particular, no effect on A beta efflux was detected when apoA-I was in mature spherical HDL, suggesting that apoA-I conformation, and lipidation could play a role in clearance from the brain. Finally, when apoA-I folded its structure in discoidal HDL, rather than in spherical ones, it was able to cross the BBB in vitro and strongly destabilize the conformation of A beta fibrils by decreasing the order of the fibril structure (-24%) and the beta-sheet content (-14%). These data suggest that the extent of apoA-I lipidation, and consequently its conformation, may represent crucial features that could exert their protective role in AD pathogenesis.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
HDL; apoA-I; beta-amyloid; Alzheimer's disease; blood-brain barrier
Elenco autori:
R. Dal Magro, S. Simonelli, A. Cox, B. Formicola, R. Corti, V. Cassina, L. Nardo, F. Mantegazza, D. Salerno, G. Grasso, M.A. Deriu, A. Danani, L. Calabresi, F. Re
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