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Molecular Pharmacology

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Research ArticleArticle

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

Anika M. S. Hartz, David S. Miller and Björn Bauer
Molecular Pharmacology May 2010, 77 (5) 715-723; DOI: https://doi.org/10.1124/mol.109.061754
Anika M. S. Hartz
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David S. Miller
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Björn Bauer
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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

  • ↵Embedded Image 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.

  • 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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Molecular Pharmacology: 77 (5)
Molecular Pharmacology
Vol. 77, Issue 5
1 May 2010
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Research ArticleArticle

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

Anika M. S. Hartz, David S. Miller and Björn Bauer
Molecular Pharmacology May 1, 2010, 77 (5) 715-723; DOI: https://doi.org/10.1124/mol.109.061754

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Research ArticleArticle

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

Anika M. S. Hartz, David S. Miller and Björn Bauer
Molecular Pharmacology May 1, 2010, 77 (5) 715-723; DOI: https://doi.org/10.1124/mol.109.061754
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