ABC Transporters and the Alzheimer's Disease Enigma

Abstract

Alzheimer's disease (AD) is considered the "disease of the twenty-first century." With a 10-fold increase in global incidence over the past 100 years, AD is now reaching epidemic proportions and by all projections, AD patient numbers will continue to rise. Despite intense research efforts, AD remains a mystery and effective therapies are still unavailable. This represents an unmet need resulting in clinical, social, and economic problems. Over the last decade, a new AD research focus has emerged: ATP-binding cassette (ABC) transporters. In this article, we provide an overview of the ABC transporters ABCA1, ABCA2, P-glycoprotein (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2), all of which are expressed in the brain and have been implicated in AD. We summarize recent findings on the role of these five transporters in AD, and discuss their potential to serve as therapeutic targets.

Keywords: ABC transporter; ABCA1; ABCA2; Alzheimer’s disease; BCRP; MRP1; P-glycoprotein; blood-brain barrier.

Figure 1

Map of the ABC transporters ABCA1, ABCA2, P-gp, MRP1, and BCRP in the CNS. Modified according to Hartz and Bauer (2011).

Figure 2

Based on current knowledge, we propose the following interplay between Aβ, ApoE, ABCA1, LRP1, P-gp, MRP1 (and possibly BCRP): Under normal physiological conditions, ABCA1-mediated cholesterol and phospholipid efflux from astrocytes, microglia, neurons (and possibly endothelial cells) facilitates ApoE lipidation. Lipidated ApoE associates with Aβ, and the ApoE-Aβ complex is taken up at the abluminal membrane of the brain capillary endothelium; this step is facilitated by LRP1. P-gp and MRP1 (and possibly BCRP) mediate Aβ efflux from the brain capillary endothelium into the blood. We postulate that a decrease in function of either ABCA1, LRP1, P-gp, or MRP1 (and possibly BCRP), or a decrease in function of some or all of these proteins reduces Aβ brain clearance, resulting in increased Aβ brain levels, which may pose a risk for AD.