Abstract
Reduced clearance of amyloid-β (Aβ) from brain partly underlies increased Aβ 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 Aβ from mouse brain capillaries into the vascular space, thus identifying a critical component of the Aβ 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 Aβ accumulates in the brain in AD. It is noteworthy that dosing 12-week-old, asymptomatic hAPP mice over 7 days with pregnenolone-16α-carbonitrile to activate the nuclear receptor pregnane X receptor restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain Aβ 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 Aβ clearance from the brain and reduce Aβ brain accumulation. This mechanism suggests a new therapeutic strategy in AD.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01-ES080048]; a Duluth Medical Research Institute Grant; and University of Minnesota College of Pharmacy startup funds.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.061754.
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ABBREVIATIONS:
- Aβ
- amyloid-β
- hAβ
- human Aβ
- AD
- Alzheimer's disease
- BCRP
- breast cancer resistance protein
- FTC
- fumitremorgin C
- hAPP
- human amyloid precursor protein
- LTC4
- leukotriene C4
- LRP1
- low-density lipoprotein receptor-related protein 1
- MRP
- multidrug resistance-associated protein
- NBD-CSA
- [N-ε (4-nitrobenzofurazan-7-yl)-d-Lys8]-cyclosporine A
- PCN
- pregnenolone-16α-carbonitrile
- PSC833
- valspodar
- PXR
- pregnane X receptor
- RAGE
- receptor for advanced glycation end products
- RAP
- receptor-associated protein
- PBS
- phosphate-buffered saline
- BSA
- bovine serum albumin
- IACUC
- Institutional Animal Care and Use Committee
- ELISA
- enzyme-linked immunosorbent assay
- GLUT-1
- glucose transporter 1.
- Received October 13, 2009.
- Accepted January 25, 2010.
- U.S. Government work not protected by U.S. copyright
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