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

Romain Versele,Andrea Fuso,Fabien Gosselet,Laurence Fenart,Pietra Candela,Emmanuel Sevin,Mariangela Corsi,Rita Businaro

doi:10.3390/ijms21030934

Romain Versele, Andrea Fuso + Show 6 more

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https://doi.org/10.3390/ijms21030934

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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.

Highlights

Affecting more than 46 million individuals worldwide, Alzheimer’s disease (AD) is considered to be the most common cause of dementia in the elderly population (World Health Organization (WHO)), with an increase of 7.7 million new cases every year
For a few years there has been an increased focus on the role of the transport of Aβ peptides across the blood–brain barrier (BBB) [4,50,51]. It appears that increasing the clearance or reducing the entry of Aβ peptides in the brain could be a promising therapeutic approach for counteracting the pathogenic processes observed in AD [52]
On the basis of ketone body (KB)’ beneficial effects on the central nervous system (CNS), and the lack of published data on the BBB, we addressed the question of whether KBs could modulate the expression of receptors/transporters implicated in the transport of Aβ across the BBB and whether these changes could impact functional transport

Summary

Introduction

Affecting more than 46 million individuals worldwide, Alzheimer’s disease (AD) is considered to be the most common cause of dementia in the elderly population (World Health Organization (WHO)), with an increase of 7.7 million new cases every year. The BBB is a physiological barrier histologically formed by endothelial cells (ECs) lining the brain microvessels [7,8] This physical barrier strictly controls the exchange of molecules between the brain and the blood in order to protect the CNS and to maintain its functioning and homeostasis [8,9]. Several members of the ATP-binding cassette (ABC) family, such as ABCB1 ( known as P-glycoprotein (P-gp)) and ABCG2 ( known as breast cancer resistance protein (BCRP)), are involved in Aβ efflux and limiting Aβ influx [13,14] Dysregulation of their expression may trigger the progressive cerebral and vascular accumulation of Aβ, as demonstrated in animal studies and clinical research [5,6,15]. Despite experimental and clinical evidence supporting the protective effect of a KD against AD [32,33] through reduced Aβ deposition and improved learning memory [34,35,36,37], little is known about the impact of this diet on BBB function

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