A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid β-Peptide from the Brain

Most data indicates that Alzheimer's disease involves an accumulation of amyloid beta-peptide (A beta) in the CNS and that sporadic cases arise from a deficiency in A beta clearance. Considerable attention has been given to mechanisms by which A beta might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in A beta transport across the blood-brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [I-125]-labeled A beta; after 60 min, homogenates of brain parenchyma were subjected to.-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography. Second, MDR1A-knockout mice were crossed with Tg2576 APP transgenic mice, a line that routinely accumulates A beta in the brain; SDS and formic acid extracts of brain homogenates were assessed for A beta levels by ELISA. Each of these approaches yielded data indicating that A beta accumulates to a greater degree in mice lacking MDR1A. These findings confirm other reports linking p-glycoprotein to A beta clearance across the BBB and have important implications for Alzheimer's disease genetics, pharmacology, and epidemiology.