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Ketone Bodies Promote Amyloid-β1-40 Clearance in a Human in Vitro Blood-Brain Barrier Model.

International journal of molecular sciences (2020-02-07)
Romain Versele, Mariangela Corsi, Andrea Fuso, Emmanuel Sevin, Rita Businaro, Fabien Gosselet, Laurence Fenart, Pietra Candela
ABSTRACT

Alzheimer's disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood-brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-GLUT-1 Antibody, CT, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Anti-Monocarboxylate Transporter 1 Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-PICALM antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, Ab1

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