Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Abstract

Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer’s disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ±6.1%, p <0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD.

Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease

“…65 These findings support the validity of increasing Aβ clearance via ABCB1 up-regulation as a therapeutic approach to slowing or halting the progression of AD.…”

“…68 In addition, in vitro and in vivo up-regulation of ABCB1 by different ABCB1 inducers significantly modulated Aβ levels. 38,65 The in vitro treatment of LS-180 cells with rifampicin, caffeine, verapamil, hyperforin, and β-estradiol, and to a lesser extent pentylenetetrazole and dexamethasone, resulted in significant decrease in the intracellular accumulation of Aβ 40 when compared to control as a result of ABCB1 up-regulation. 38 Furthermore, in vivo BEI% studies conducted on C57BL/6 mice treated with rifampicin or caffeine significantly enhanced Aβ 40 clearance by more than 20% when compared to control vehicle treated mice.…”

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

“…In addition, dissolving the vascular deposits could also lead to disruption of the vessel wall, increasing the chance of hemorrhages. The clearance of soluble Aβ could be stimulated by the widely used drugs caffeine and rifampicin, as these drugs both upregulate the blood brain barrier transporter P-glycoprotein, and rifampicin also upregulates LRP1 in wild-type mice (Qosa et al, 2012). As the proteolytic degradation of soluble Aβ is stimulated by ApoE, Cramer and colleagues hypothesized that enhancement of ApoE expression with the retinoid X receptor agonist bextarotene could promote Aβ clearance and microglial phagocytosis.…”

The ABCB1 Transporter in Alzheimer’s Disease

“…One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters. Several BBB transporters have been implicated in Aβ exchange between brain parenchyma and the circulation [5][6][7][8][9][10][11][12]. Deficiency of either of the two major efflux pumps, ABCB1 and ABCG2, involved in Aβ trafficking across the BBB, results in increased accumulation of peripherallyinjected Aβ in the brain [13].…”

“…ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the BBB and brain parenchyma, affect Aβ transport (flux) across the BBB contributing to the pathogenesis of Alzheimer's disease (AD) [5][6][7][8][9][10][11][12]. One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters.…”