Restoring Blood-Brain Barrier P-Glycoprotein Reduces Brain Amyloid-β in a Mouse Model of Alzheimer's Disease

Abstract

Reduced clearance of amyloid-␤ (A␤) from brain partly underlies increased A␤ brain accumulation in Alzheimer's disease (AD). The mechanistic basis for this pathology is unknown, but recent evidence suggests a neurovascular component in AD etiology. We show here that the ATP-driven pump, P-glycoprotein, specifically mediates efflux transport of A␤ from mouse brain capillaries into the vascular space, thus identifying a critical component of the A␤ brain efflux mechanism. We demonstrate in a transgenic mouse model of AD [human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576 strain] that brain capillary P-glycoprotein expression and transport activity are substantially reduced compared with wild-type control mice, suggesting a mechanism by which A␤ accumulates in the brain in AD. It is noteworthy that dosing 12-week-old, asymptomatic hAPP mice over 7 days with pregnenolone-16␣-carbonitrile to activate the nuclear receptor pregnane X receptor restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain A␤ levels compared with untreated control mice. Thus, targeting intracellular signals that up-regulate blood-brain barrier P-glycoprotein in the early stages of AD has the potential to increase A␤ clearance from the brain and reduce A␤ brain accumulation. This mechanism suggests a new therapeutic strategy in AD.A hallmark of Alzheimer's disease (AD) is the accumulation of neurotoxic amyloid-␤ (A␤) peptide within the brain. The A␤ transport-clearance hypothesis of AD proposed by Zlokovic and coworkers (Zlokovic and Frangione, 2003;Deane et al., 2004b;Zlokovic, 2005) states that reduced A␤ clearance (reduced A␤ efflux transport) from the brain underlies A␤ brain accumulation (see also Mooradian et al., 1997). This hypothesis suggests that the mechanism responsible for A␤ brain clearance itself could be a therapeutic target in AD.A␤ clearance from brain to blood has to be a two-step process. A␤ must first pass through the abluminal (brain side) and then the luminal (blood side) plasma membranes of the brain capillary endothelial cells that comprise the bloodbrain barrier. Given that A␤ is a peptide, both steps must be facilitated, involving receptors or transporters. At the abluminal membrane, the receptor low-density lipoprotein receptor-related protein 1 (LRP1) seems to be the major protein responsible for A␤ uptake from brain into capillary endothelial cells (Shibata et al., 2000; Deane et al., 2004a,b). However, the luminal membrane protein mediating the critical second step, A␤ efflux from the endothelial cells into the blood, has not been identified.One candidate is P-glycoprotein, an ATP-driven efflux transporter that under normal physiological conditions is highly expressed at the luminal membrane of the brain capillary endothelium. This transporter handles a wide spectrum of nonpolar, therapeutic drugs, some of which are small polypeptide derivatives .

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…Amyloid-b also decreases microvascular expression of its transporters. This is evident for LRP-1 and Pgp in transgenic mouse models of AD, 63,71 and in nontransgenic mice treated with Ab. 73 Impaired Ab efflux is also observed in the SAMP8 mouse model of AD, which derives from a spontaneous mutation found to cause accelerated senescence.…”

“…64 Because of its luminal location, 65 it has been proposed that Pgp facilitates the extrusion of Ab from the endothelial cell into the bloodstream after Ab has been internalized from brain interstitial fluid (ISF) by LRP-1. 63 However, our group has found that under inflammatory conditions, antioxidant treatment that preserves LRP-1 but not Pgp function also preserves Ab efflux. 66 This suggests that LRP-1 can also function independently of Pgp.…”

“…One example is the multidrug transporter P-glycoprotein (Pgp). Evidence supporting this role for Pgp includes: (1) observations of Pgp-dependent efflux of Ab in vitro, 59,60 (2) an inverse correlation of Ab deposition and microvascular Pgp expression in human brain tissue, 61 (3) decreased Ab efflux and enhanced Ab deposition in mice that lack Pgp, 62 (4) impaired microvascular Pgp function in a transgenic AD mouse model that is restored by pharmacologic intervention shows corresponding improvement in Ab efflux and reduced Ab deposition, 62,63 and (5) showing Pgp dysfunction in human AD using clinical PET imaging studies. 64 Because of its luminal location, 65 it has been proposed that Pgp facilitates the extrusion of Ab from the endothelial cell into the bloodstream after Ab has been internalized from brain interstitial fluid (ISF) by LRP-1.…”

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

“…For example, in vivo induction of ABCB1 expression at the BBB of hAPP transgenic mice via PXR activation significantly reduced Aβ deposition in the mice brains as a result of increased ABCB1 mediated Aβ efflux across the luminal membrane of the BBB. 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.…”

Concentration of donepezil in the cerebrospinal fluid of AD patients: Evaluation of dosage sufficiency in standard treatment strategy

“…According to previously published studies, P-gp (P-glycoprotein) is an important determinant for the disposition of donepezil, influencing its efflux from the central compartment to the blood stream (Ishiwata et al 2007). It should be noted that BBB P-gp is degraded in the progressive pathogenesis of AD and hence a higher CSF donepezil concentration may be found in patients in an advanced stage of the disease (Hartz et al 2010).…”