Beta-Amyloid Downregulates MDR1-P-Glycoprotein (Abcb1) Expression at the Blood-Brain Barrier in Mice

Abstract

Neurovascular dysfunction is an important component of Alzheimer's disease, leading to reduced clearance across the blood-brain barrier and accumulation of neurotoxic β-amyloid (Aβ) peptides in the brain. It has been shown that the ABC transport protein P-glycoprotein (P-gp, ABCB1) is involved in the export of Aβ from the brain into the blood. To determine whether Aβ influences the expression of key Aβ transporters, we studied the effects of 1-day subcutaneous Aβ1-40 and Aβ1-42 administration via Alzet mini-osmotic pumps on P-gp, BCRP, LRP1, and RAGE expression in the brain of 90-day-old male FVB mice. Our results demonstrate significantly reduced P-gp, LRP1, and RAGE mRNA expression in mice treated with Aβ1-42 compared to controls, while BCRP expression was not affected. The expression of the four proteins was unchanged in mice treated with Aβ1-40 or reverse-sequence peptides. These findings indicate that, in addition to the age-related decrease of P-gp expression, Aβ1-42 itself downregulates the expression of P-gp and other Aβ-transporters, which could exacerbate the intracerebral accumulation of Aβ and thereby accelerate neurodegeneration in Alzheimer's disease and cerebral β-amyloid angiopathy.

Figure 1

mRNA expression of Abcb1a (a), Abcg2 (b), LRP1 (c), and RAGE (d) in murine brain. Mice were treated with β-amyloid 1-42 (Aβ1-42), reverse β-amyloid 42-1 (Aβ42-1) and vehicle control (control) using ALZET pumps for 24 h (4 μg/h). mRNA expression of each transporter was normalized to 18S rRNA expression and values are depicted in relation to the median expression in vehicle perfused mice. Statistical analysis was performed by one-way ANOVA followed by Newmann-Keuls Multiple Comparison test.

Figure 2

mRNA expression of Abcb1a (a), Abcg2 (b), LRP1 (c) and RAGE (d) in murine brain. Mice were treated with β-amyloid 1-40 (Aβ1-40), reverse-sequence β-amyloid 40-1 (Aβ40-1) and vehicle control (control) using ALZET pumps for 24 h (4 μg/h). mRNA expression of each transporter was normalized to 18S rRNA expression, and values are depicted in relation to the median expression in vehicle-perfused mice. Statistical analysis was performed by one-way ANOVA followed by Newmann-Keuls Multiple Comparison test.

Figure 3

Immunohistochemical expression of P-gp (a) and BCRP (b) in endothelial cells of mice brain capillaries (original magnification ×200).