Abundance of P-Glycoprotein and Other Drug Transporters at the Human Blood-Brain Barrier in Alzheimer's Disease: A Quantitative Targeted Proteomic Study

The human blood-brain barrier (BBB) transporter P-gp can efflux amyloid-beta (A beta) out of the central nervous system (CNS). A beta is thought to be the causative agent for Alzheimer's disease (AD). Using positron emission tomography imaging, we have shown that BBB P-gp activity is reduced in AD, as quantified by thein vivobrain distribution of the P-gp probe [C-11]-verapamil. Therefore, the aim of this study was to determine whether this reduced BBB P-gp activity in AD was due to decreased P-gp abundance at the BBB. Using targeted proteomics, we quantified the abundance of P-gp and other drug transporters in gray matter brain microvessels isolated from 43 subjects with AD and 38 age-matched controls (AMCs) from regions affected by AD (hippocampus and the parietal lobe of the brain cortex) and not affected by AD (cerebellum). First, P-gp abundance was decreased in the BBB of the hippocampus vs. the cerebellum in both subjects with AD and AMCs, and therefore was not AD-related. In addition, gray matter BBB abundance of P-gp (and of other transporters) in the hippocampus and the parietal lobe was not different between AD and AMC. The gray matter BBB abundance of all drug transporters decreased with age, likely due to age-dependent decrease in the density of brain microvessels. Collectively, the observed reducedin vivocerebral BBB P-gp activity in AD cannot be explained by reduced abundance of P-gp at the BBB. Nevertheless, the drug transporter abundance at the human gray matter BBB data provided here can be used to predict brain distribution of drugs targeted to treat CNS diseases, including AD.

Automated summary

The study found that the abundance of P-gp in the BBB of the hippocampus was decreased in both subjects with AD and age-matched controls, but it was not related to AD. Additionally, the abundance of P-gp in gray matter BBB of the hippocampus and parietal lobe was not different between AD and controls. The abundance of all drug transporters at the gray matter BBB decreased with age, likely due to age-dependent decrease in brain microvessel density.