Dataset Information

Ketone Bodies Promote Amyloid-?1-40 Clearance in a Human in Vitro Blood-Brain Barrier Model.

ABSTRACT: Alzheimer's disease (AD) is characterized by the abnormal accumulation of amyloid-? (A?) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of A? 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 A? load in the AD brain, little information is available about the effect of KBs on BBB and their effect on A? 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 A? 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 A? clearance. Finally, the combined use of KBs promotes A? efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote A? clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.

SUBMITTER: Versele R

PROVIDER: S-EPMC7037612 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Ketone Bodies Promote Amyloid-β<sub>1-40</sub> Clearance in a Human in Vitro Blood-Brain Barrier Model.

Versele Romain R Corsi Mariangela M Fuso Andrea A Sevin Emmanuel E Businaro Rita R Gosselet Fabien F Fenart Laurence L Candela Pietra P

International journal of molecular sciences 20200131 3

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 ...[more]

PMID: 32023814

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Project description:Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes Aβ clearance across BBB.

Dataset Information

Ketone Bodies Promote Amyloid-?1-40 Clearance in a Human in Vitro Blood-Brain Barrier Model.

Publications

Ketone Bodies Promote Amyloid-β<sub>1-40</sub> Clearance in a Human in Vitro Blood-Brain Barrier Model.

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