Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer's disease

• Published in: Molecular pharmacology 2010-05, Vol.77 (5), p.715-723
• Main Authors: Hartz, Anika M S, Miller, David S, Bauer, Björn
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological Transport; Blood-Brain Barrier; Capillaries - metabolism; Cerebrovascular Circulation - physiology; Disease Models, Animal; Humans; Male; Mice; Mice, Transgenic; Peptide Fragments - metabolism; Protease Nexins; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.109.061754

Reduced clearance of amyloid-beta (Abeta) from brain partly underlies increased Abeta 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 Abeta from mouse brain capillaries into the vascular space, thus identifying a critical component of the Abeta 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 Abeta accumulates in the brain in AD. It is noteworthy that dosing 12-week-old, asymptomatic hAPP mice over 7 days with pregnenolone-16alpha-carbonitrile to activate the nuclear receptor pregnane X receptor restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain Abeta 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 Abeta clearance from the brain and reduce Abeta brain accumulation. This mechanism suggests a new therapeutic strategy in AD.