RT Journal Article
SR Electronic
T1 Restoring Blood-Brain Barrier P-glycoprotein Reduces Brain Aβ in a Mouse Model of Alzheimer's Disease
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.061754
DO 10.1124/mol.109.061754
A1 Anika Maria Sophie Hartz
A1 David S. Miller
A1 Bjoern Bauer
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/02/26/mol.109.061754.abstract
AB 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 to wild type control mice, suggesting a mechanism by which Aβ accumulates in the brain in AD. Importantly, we show that dosing 12-week old, asymptomatic hAPP mice over 7 days with pregnenolone-16α-carbonitrile (PCN) to activate the nuclear receptor, pregnane X receptor (PXR), restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain Aβ levels compared to untreated control mice. Thus, targeting intracellular signals that up-regulate blood-brain barrier P-glycoprotein in 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.The American Society for Pharmacology and Experimental Therapeutics